Compositions and methods for inhibition of ras

Abstract

This document provides compounds or their salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers, and pharmaceutical compositions comprising the above. This document also provides methods for using the above to modulate (e.g., inhibit) KRAS (e.g., KRAS with a G12D mutation) and treat diseases or conditions (such as cancer) in individuals in need.

Description

Prior Technology

[0001] RAS mutations occur in approximately 20-30% of human cancers, including most pancreatic ductal adenocarcinomas (PDAC), half of colorectal cancers, and one-third of all lung cancers. With the highest RAS mutation frequency observed among 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 a major challenge in cancer research. RAS proteins do not appear to provide suitable pockets for drug binding other than the GDP / GTP binding site. Unfortunately, RAS proteins bind to these nucleotides with extremely high (picomole) affinity, making the development of effective nucleotide analogs nearly impossible. Attempts to block pathways downstream of RAS in the hope of providing clinical benefit to patients with RAS-driven cancers have generally been disappointing. Recently, allele-specific covalent KRAS G12C inhibitors entered clinical trials, and early clinical data show at least some efficacy in lung cancer.

[0002] The three RAS genes (HRAS, NRAS and KRAS) encode four 188-189 amino acid proteins, which share 82%-90% amino acid sequence identity and almost identical structural and biochemical properties. However, these genes are differentially mutated and mutated at different frequencies in cancer. KRAS is the most frequently mutated oncogene in cancer, and KRAS mutations are often associated with poor prognosis and resistance to therapy. Significant cancer type preference exists among RAS genes. KRAS mutations predominate in lung, colorectal, and pancreatic cancers, while NRAS mutations predominate in cutaneous melanoma and acute myelogenous leukemia, and HRAS mutations are found in bladder and head and neck squamous cell carcinomas.

[0003] KRAS is mutated and activated in 94% of pancreatic cancers. Pancreatic cancer, such as pancreatic ductal adenocarcinoma (PDAC), was the third leading cause of cancer death in the United States in 2016. As the incidence continues to increase, pancreatic cancer is expected to become the second leading cause of cancer death by 2020. Pancreatic cancer is the deadliest cancer in the United States due to the absence of biomarkers for early detection, late onset of symptoms when the cancer has reached a metastatic state, and an 8% 5-year survival rate.

[0004] KRAS mutation is the initial genetic step in pancreatic cancer; however, continued mutation of KRAS function is required to maintain PDAC growth. RNA interference-mediated inactivation of KRAS in KRAS G12D-driven PDAC showed rapid regression of tumor growth. These data support the importance of mutant KRAS as a therapeutic target for PDAC. Since 40% of PDAC is driven by the KRAS G12D mutant, inhibitors targeting this mutation are highly desired. KRAS G12D mutations also occur at high frequency in lung and colorectal cancers, making KRAS G12D an ideal therapeutic target for direct G12D allele-specific inhibitors.

Content of invention

[0006] In one aspect, the disclosure provides compositions comprising a compound represented by formula I or formula II: (I) (II) or a salt, ester, tautomer, former Drugs, zwitterionic forms or stereoisomers, wherein R1, R2, R3, R4, R5, R6 and R7 are as provided herein. In some embodiments, a compound provided herein, or a salt, ester, tautomer, zwitterionic form or stereoisomer thereof, modulates the activity of a KRAS protein, such as a KRAS protein with a G12D mutation.

[0007] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by Formula I or Formula II and a pharmaceutically acceptable carrier.

[0008] In yet another aspect, the disclosure provides a method of inhibiting KRAS activity in a human or animal subject for use in the treatment of diseases, such as cancer, including pancreatic cancer (e.g., pancreatic ductal adenocarcinoma ( PDAC )), colorectal and lung cancers.

[0009] In another aspect, the disclosure provides a use of a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, for the manufacture of Agents for ameliorating, treating, inhibiting or alleviating a disease, disorder or disorder (eg cancer) by inhibiting KRAS, including KRAS with a G12D mutation. In some embodiments, the disease, disorder or condition is pancreatic cancer (eg, pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer or lung cancer.

[0010] In yet another aspect, the disclosure provides a compound as provided herein, or a salt, ester, tautomer, zwitterionic form or stereoisomer thereof, for use as a medicament. In some embodiments, the medicament is used to treat a disease, disorder or condition (eg, cancer). In some embodiments, the disease, disorder or condition is pancreatic cancer (eg, pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer or lung cancer.

Implementation

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

[0013] When a range of values ​​is disclosed and the notation "n1...to n2" or "between n1...and n2" (where n1 and n2 are numbers) is used, unless otherwise specified, otherwise This notation is intended to include both the numbers themselves and the ranges in between. The range can be an integer or continuous between and inclusive of the endpoints. For example, the range "2 to 6 carbons" is intended to include two, three, four, five and six carbons, since carbons occur in integer units. For example, compare the range "1 to 3 µM (micromole)" (which range is intended to include 1 µM, 3 µM, and all numbers in between) to any number with significant digits (e.g., 1.255 µM, 2.1 µM, 2.9999 µM etc.).

[0014] As used herein, "about" is intended to qualify the value it modifies, expressing such value as a variable within a margin of error. When a specific margin of error is not recited, such as the standard deviation from the mean given in a graph or data table, the term "about" should be understood to mean that the range of stated values ​​will be encompassed and taking into account that significant digits will be calculated by rounding to Those digits are also included in the range.

[0015] As used herein, "acyl" alone or in combination refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle or any other moiety, wherein the carbonyl group attached to the carbonyl The atom is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanyl" group means an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkacyl and aryl.

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

[0017] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one parameter bond with the indicated number of carbon atoms (ie, C2-6 means two to six carbons). Alkynyl groups can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6 and C6. Examples of alkynyl include, but are not limited to, ethynyl, 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-hexanedi Alkynyl, 1,5-hexadiynyl, 2,4-hexadiynyl and 1,3,5-hexatriynyl.

[0018] As used herein, "alkoxy", alone or in combination, refers to an alkyl ether group, wherein the term alkyl is as described herein. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, and Similar groups.

[0019] As used herein, "alkyl" alone or in combination refers to a straight or branched chain alkyl group (such as a C1-20 alkyl group) containing 1 to 20 carbon atoms. In certain embodiments, the alkyl group will contain 1 to 10 carbon atoms (eg, C1-10 alkyl). In further embodiments, the alkyl group will contain 1 to 8 carbon atoms (eg, C1-8 alkyl). In further embodiments, the alkyl group will contain 1 to 6 carbon atoms (eg, C1-6 alkyl). In further embodiments, the alkyl group will contain 1 to 3 carbon atoms (eg, C1-3 alkyl). Alkyl groups are unsubstituted or substituted, as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, hexyl, octyl, nonyl group and its analogues. As used herein, the term "alkylene" alone or in combination refers to a saturated aliphatic group derived from a linear or branched saturated hydrocarbon attached at two or more positions, such as methylene (-CH2- ). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

[0020] As used herein, "alkylamino" alone or in combination refers to an alkyl group attached to the parent molecular moiety through an amine group. Suitable alkylamine groups may be mono- or di-alkylated, forming groups such as N-methylamine, N-ethylamine, N,N-dimethylamine, N,N-ethylamine, A group of a methylamino group and a group similar to it.

[0021] As used herein, "alkylthio" alone or in combination refers to an alkylsulfide (R-S-) group, wherein the term alkyl is as described herein and wherein the sulfur may be mono- or di-oxidized. Examples of suitable alkylthioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, secondary butylthio, tertiary butylthio , methanesulfonyl, ethanesulfinyl and the like.

[0022] As used herein, "amido" and "carbamoyl", alone or in combination, refer to an amine group as described herein attached to the parent molecular moiety through a carbonyl group, and 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, wherein R and R' are as defined herein or specified by a specific enumeration of "R" defined by the group. In some embodiments, the "amido" group includes -C(O)NH2, C1-4 alkylamido and bis(C1-4 alkyl)amido. As used herein, the term "C1-4 alkylamido" refers to -C(O)NH(C1-4 alkyl), wherein C1-4 alkyl is as defined herein. As used herein, the term "N-amido", alone or in combination, refers to a RC(O)N(R')- group, wherein R and R' are as defined herein or specified by a specific enumeration of "R" defined by the group. As used herein, the term "acylamino" alone or in combination includes an acyl group attached to the parent moiety through an amine group. An example of an "acylamino" group is acetamido (CH3C(O)NH-).

[0023] As used herein, "amino" alone or in combination refers to -NRR', wherein R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, Heteroaryl and heterocycloalkyl, either of which may itself be unsubstituted or substituted. Additionally, R and R' may combine to form unsubstituted or substituted heterocycloalkyl. The "amino" group can be a primary amine (eg -NH2), a secondary amine or a disubstituted amine (eg -NHR, where R is other than hydrogen), or a tertiary or trisubstituted amine (eg -NRR', wherein neither R nor R' is hydrogen).

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

[0025] As used herein, "arylalkenyl" or "arylalkenyl", alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0026] As used herein, "arylalkoxy" or "aralkoxy", alone or in combination, refers to an aryl group appended to the parent molecular moiety through an alkoxy group.

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

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

[0029] As used herein, "carbamate," alone or in combination, refers to an ester of carbamic acid (-NHCOO-), which may be attached to the parent molecular moiety from the nitrogen or acid terminus, and which, as defined herein, is not Substituted or substituted.

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

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

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

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

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

[0035] As used herein, "cycloalkyl" or alternatively "carbocycle" alone or in combination refers to a saturated or partially saturated monocyclic, bicyclic or tricycloalkyl group wherein each cyclic moiety contains from 3 to 12 carbons Atom ring members and which may optionally be benzofused ring systems, unsubstituted or substituted as defined herein. Carbocycles can include bridged ring systems and / or spiro ring systems (eg, systems comprising two rings sharing a single carbon atom). The term "cycloalkenyl" refers to a cycloalkyl group having one or two double bonds. In certain embodiments, the cycloalkyl (or cycloalkenyl) will contain 5 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydronaphthyl, indenyl , octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and similar groups. As used herein, "bicyclic" and "tricyclic" are intended to include fused ring systems, such as decahydronaphthalene and octahydronaphthalene, as well as polycyclic (multicenter) saturated or partially unsaturated types. Isomers of the latter type are generally exemplified by bicyclo[1,1,1]pentane, camphor, adamantane and bicyclo[3,2,1]octane.

[0036] As used herein, "ester", alone or in combination, refers to a carboxyl group bridging two moieties linked at carbon atoms.

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

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

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

[0040] As used herein, "haloalkyl", alone or in combination, refers to an alkyl group having the meaning described herein, wherein one or more hydrogens are replaced by a halogen. Monohaloalkyl, dihaloalkyl and polyhaloalkyl are specifically contemplated. For example, a monohaloalkyl group can have iodine, bromine, chlorine or fluorine atoms within the group. Dihaloalkyl and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, Dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0041] As used herein, "heteroalkyl" alone or in combination refers to a stable linear or branched hydrocarbon chain, fully saturated or containing 1 to 3 degrees of unsaturation, selected from the specified number of carbon atoms and from one to three Composed of heteroatoms from N, O and S, wherein the N and S atoms are optionally oxidized and the N heteroatoms are optionally quaternized. A heteroatom can be located at any internal position within a heteroalkyl group. Up to two heteroatoms can be consecutive, such as -CH2-NH-OCH3.

[0042] As used herein, "heteroaryl", alone or in combination, refers to a 3 to 15 membered aromatic monocyclic ring, or a fused monocyclic, bicyclic or tricyclic ring system, wherein at least one fused ring is aromatic, the A ring or ring system contains at least one atom selected from N, O and S. In certain embodiments, the heteroaryl will contain 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl will contain 5 to 7 atoms. The term also encompasses fused polycyclic groups wherein a heterocycle is fused to an aryl ring, wherein a heteroaryl ring is fused to another heteroaryl ring, wherein a heteroaryl ring is fused to a heterocycloalkyl ring, or wherein the 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, oxazolyl, Diazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indorazinyl, benzimidazolyl, quinolinyl, isoquinolyl, quinoxalinyl, quinolyl Azolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzofuryl, benzothienyl, chromone, coumarinyl, benzopyranyl, tetrahydroquinolyl, tetrazolopyridazinyl, tetrahydroisoquinolyl , thienopyridyl, furopyridyl, pyrrolopyridyl and the like. Exemplary tricyclic heterocyclyl groups include carbazolyl, phenanthrenyl, dibenzofuryl, acridinyl, phenanthridinyl, dibenzopyranyl, and the like.

[0043] As used herein, "heterocycloalkyl" and interchangeably "heterocycle", alone or in combination, each refer to a saturated, partially unsaturated or fully unsaturated (but not Aromatic) monocyclic, bicyclic or tricyclic heterocyclyl, wherein each of the heteroatoms can be independently selected from nitrogen, oxygen and sulfur. In certain embodiments, the heterocycloalkyl will contain 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl will comprise 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will comprise 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl will comprise 3 to 7 ring members in each ring. In still further embodiments, the heterocycloalkyl will comprise 5 to 6 ring members in each ring. Heterocyclic rings may include bridged ring systems and / or spiro ring systems (eg, systems comprising two rings that share a single atom, such as a single carbon atom). "Heterocycloalkyl" and "heterocycle" are intended to include arone, arylene, N-oxides of tertiary nitrogen ring members, and carbocyclic-fused and benzo-fused ring systems; in addition, both terms include Systems in which the heterocycle is fused to an aryl or additional heterocyclyl as defined herein. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolyl, dihydrocinnolinyl, Linyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridyl, benzothiazolyl, indolinyl, dihydropyridyl , 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetra Hydropyridyl, piperidyl, thiomorpholinyl and the like. Unless specifically prohibited, a heterocyclyl group is unsubstituted or substituted.

[0044] As used herein, "hydrazino" alone or in combination refers to two amine groups connected by a single bond, ie, -N-N-.

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

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

[0047] As used herein, "iminohydroxy" alone or in combination refers to =N(OH) and =N-O-.

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

[0049] As used herein, "mercapto" alone or in combination refers to a RS- group, wherein R is as defined herein.

[0050] As used herein, "nitro" alone or in combination refers to -NO2.

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

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

[0053] "Perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0054] As used herein, "perhaloalkyl" alone or in combination refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0055] As used herein, a "ring" or equivalently a "cycle" with respect to a chemical structure or portion thereof refers to a group in which each atom is a member of a common ring structure. Unless otherwise specified, rings can be saturated or unsaturated, include aromatic, and can have from 3 to 9 members. If the ring is heterocyclic, it may contain 1 to 4 heteroatoms or heteroatom-containing groups selected from B, N, O, S, C(O), S(O)m. Rings are unsubstituted or substituted unless specifically prohibited. Two or more rings can be fused together (eg, they can share a bond and two atoms in common). Two or more rings can be linked together in a spiro arrangement such that only a single atom is shared between the two rings. Two or more rings may also or alternatively be configured in a bridged arrangement such that three or more atoms are shared between the two or more rings.

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

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

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

[0059] As used herein, "sulfonyl" alone or in combination refers to -S(O)2-.

[0060] "N-sulfonylamino" refers to a RS(=0)2NR'-group, wherein R and R' are as defined herein.

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

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

[0063] As used herein, "thia" and "thio" alone or in combination refer to a -S- group or an ether in which the oxygen is replaced by sulfur. Oxidized derivatives of thio, ie, sulfinyl and sulfonyl, are included within the definition of thia and thio.

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

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

[0066] "N-Thiaminoformyl" refers to a ROC(S)NR'- group, wherein R and R' are as defined herein.

[0067] "O-Thiaminoformyl" refers to a -OC(S)NRR' group, wherein R and R' are as defined herein.

[0068] "thiocyanato" refers to a -CNS group.

[0069] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is the element connected to the parent part. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through the amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through the alkyl group.

[0070] As described herein, a group can be substituted or unsubstituted (eg, "optionally substituted"). Unless otherwise specified, any group may be substituted with one or more substituents, such as one or more of those provided herein. Examples of substituents for substitutable groups include, but are not limited to, one or more substituents independently selected from the following groups or groups of specified groups, alone or in combination: alkyl (eg, C1-20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl, such as C1-3 alkyl), alkenyl (such as C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl), alkynyl (such as C2-20 alkynyl, such as C2-10 alkynyl, such as C2-6 alkynyl), alkacyl (for example C1-20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl), Heteroalkyl (for example heteroalkyl moieties comprising 1-20 carbon atoms and 1-6 heteroatoms, such as heteroalkyl moieties comprising 1-6 carbon atoms and 1-3 heteroatoms), haloalkyl (such as C1-20 alkyl substituted by halo, such as C1-10 alkyl substituted by halo, C1-6 alkyl substituted by halo), haloalkenyl (such as C2-20 alkenyl substituted by halo, such as Halo-substituted C2-6 alkenyl), haloalkynyl (such as halo-substituted C2-20 alkynyl, such as halo-substituted C2-6 alkynyl), perhaloalkyl (such as C1-20 perhaloalkane group, such as C1-6 perhaloalkyl, such as C1-3 perhaloalkyl), perhaloalkoxy (such as C1-20 perhaloalkoxy, such as C1-6 perhaloalkoxy), phenyl , aryl (eg C5-20 aryl, such as C5-10 aryl, such as C5-6 aryl), aryloxy (eg C5-20 aryloxy, such as C5-10 aryloxy, such as C5-6 aryloxy), alkoxy (e.g. C1-20 alkoxy, such as C1-10 alkoxy, such as C1-6 alkoxy), haloalkoxy (e.g. C1-20 haloalkoxy, such as C1 -10 haloalkoxy, such as C1-6 haloalkoxy), pendant oxy, acyloxy (for example including 1-20 carbon atoms, such as 1-10 carbon atoms, such as 1-6 carbon atoms Acyloxy), carbonyl (for example C(O) or C=O), carboxyl (for example C(O)O), alkylcarbonyl (for example C1-20 alkylcarbonyl, such as C1-10 alkylcarbonyl, such as C1 -6 alkylcarbonyl, such as C1-3 alkylcarbonyl), carboxyl ester (for example C (O) OR, wherein R is for example alkyl (for example C1-20 alkyl, such as C1-10 alkyl, such as C1-6 Alkyl, such as C1-3 alkyl), alkenyl (such as C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl) or alkynyl (such as C2-20 alkynyl, such as C2-10 alkynyl, such as C2-6 alkynyl), any of which may be substituted by any of the groups provided herein), carboxamido, cyano (eg CN), hydrogen, halogen (eg iodo, bromo, chloro, or fluorine), hydroxyl, amino (such as NR'R", wherein R' and R" are independently such as hydrogen, alkyl (such as C1-20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl, Such as C1-3 alkyl), alkenyl (for example C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl) or alkynyl (for example C2-20 alkynyl, such as C2-10 alkynyl, such as C2-6 alkynyl), any of which may be substituted by any of the groups provided herein), alkylamine (eg NR'R", wherein R' is alkyl (eg C1-20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl, such as C1-3 alkyl) and R" is for example hydrogen, alkyl (for example C1-20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl , such as C1-3 alkyl), alkenyl (such as C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl) or alkynyl (such as C2-20 alkynyl, such as C2-10 alkynyl , such as C2-6 alkynyl), any of which may be substituted by any of the groups provided herein), arylamine (eg NR'R", wherein R' is aryl (eg C5-20 aryl, such as C5-10 aryl, such as C5-6 aryl) and R" is e.g. hydrogen, alkyl (e.g. C1-20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl, such as C1-3 alk group), alkenyl (for example C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl) or alkynyl (for example C2-20 alkynyl, such as C2-10 alkynyl, such as C2-6 alkyne group), any of which may be substituted by any of the groups provided herein), amido group (such as C(O)NR'R", wherein R' and R" are independently such as hydrogen, alkyl group (such as C1 -20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl, such as C1-3 alkyl), alkenyl (for example C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl ) or alkynyl (eg C2-20 alkynyl, such as C2-10 alkynyl, such as C2-6 alkynyl), any of which may be substituted by any of the groups provided herein), nitro (eg NO2), Thiol (such as SH), alkylthio (such as C1-20 alkyl substituted by thiol, such as C1-10 alkyl substituted by thiol, such as C1-6 alkyl substituted by thiol, Such as C1-3 alkyl substituted by thiol), haloalkylthio (for example C1-20 haloalkylthio, such as C1-10 haloalkylthio, such as C1-6 haloalkylthio, such as C1-3 Haloalkylthio), perhaloalkylthio (for example C1-20 perhaloalkylthio, such as C1-10 perhaloalkylthio, such as C1-6 perhaloalkylthio, such as C1-3 perhaloalkylthio base), aryl thiol (for example C5-20 aryl thiol, such as C5-10 aryl thiol, such as C5-6 aryl thiol), sulfonate (for example S(O)2OR, wherein R is For example alkyl (for example C1-20 alkyl, such as C1-10 alkyl, such as C1-6 alkyl, such as C1-3 alkyl), alkenyl (for example C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl) or alkynyl (e.g. C2-20 alkynyl, such as C2-10 alkynyl, such as C2-6 alkynyl), either of which may be substituted by any of the groups provided herein), sulfo Acids (such as S(O)2OH), trisubstituted silicon groups (such as SiR'R"R*, wherein R', R" and R* are independently selected from, for example, alkyl groups (such as C1-20 alkyl groups, such as C1-10 alkyl, such as C1-6 alkyl, such as C1-3 alkyl), alkenyl (such as C2-20 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl) or alkynyl (such as C2-20 alkynyl, such as C2-10 alkynyl, such as C2-6 alkynyl), any of which may be substituted by any of the groups provided herein; in some cases, the trisubstituted silyl group may be trimethyl Silyl), N3, SCH3, C(O)CH3, CO2CH3, CO2H, pyridyl, thiophene, furyl, carbamate and urea. Additional groups are also contemplated. Where structurally feasible, two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms (e.g., N, O, S, etc.) ring, for example to form methylenedioxy or ethylenedioxy. Unsubstituted or substituted groups can be unsubstituted (eg, -CH2CH3), fully substituted (eg, -CF2CF3), monosubstituted (eg, -CH2CH2F), or substituted at levels in between fully substituted and monosubstituted (eg -CH2CF3). Where a substituent is stated without limitation, both substituted and unsubstituted forms are contemplated. Where a substituent is defined as "substituted," substituted forms are specifically contemplated. In addition, different sets of optional substituents for a particular moiety may be defined as desired; in such cases, the optional substitutions will be as defined, usually immediately following the phrase "unsubstituted or substituted".

[0071] Unless otherwise defined, the terms R, R', R", R*, etc. appearing alone and without a numerical designation refer to the group selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl groups, either of which are unsubstituted or substituted (eg, as described herein). Such R and R' groups are understood to be unsubstituted or substituted as defined herein. Regardless of whether the R group has a numerical designation, each R group, including R, R', and Rn (where n=(1, 2, 3, ... n)), each substituent, and each term is understood to be The selection aspects from the group are independent of each other. If any variable, substituent or term (such as aryl, heterocycle, R, etc.) occurs more than once in a formula or general structure, its definition at each occurrence is independent of each Other Definitions Where Occurrences. Those skilled in the art will further recognize that certain groups may be attached to the parent molecule or may occupy a position in a chain of elements from either end as written. For example, such as -C(O) An N(R)- asymmetric group can be attached to the parent moiety at carbon or nitrogen.

[0072] "Bond" means a covalent bond between two atoms, or when the atoms joined by the bond are considered part of a larger substructure. Unless otherwise specified, a bond can be single, double, or parabond. A dashed line between two atoms in a molecular diagram indicates that an additional bond may or may not be present at that position.

[0073] Asymmetric centers may exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. It is to be understood that the present disclosure encompasses all stereochemical isomeric forms, including diastereoisomers, enantiomers, atropisomers, and epimeric forms, as well as d-isomers and 1 - Isomers, and mixtures thereof. Individual stereoisomers of compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparation of mixtures of enantiomeric products followed by separation, such as conversion into diastereomers The mixture is prepared by subsequent separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral column or any other suitable method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be prepared and resolved by techniques known in the art. In addition, the compounds disclosed herein may exist as geometric isomers. The disclosure includes all cis, trans, syn, anti, hetero (E) and homo (Z) isomers and appropriate mixtures thereof. Additionally, compounds may exist in tautomeric forms; all tautomers are provided by this disclosure. Additionally, the compounds provided herein may contain conformational isomers, which compounds include groups that can be oriented in a different configuration relative to another moiety. In addition, 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, the solvated forms are considered equivalent to the unsolvated forms.

[0074] "Combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic disorder or condition described in this disclosure. Such administration encompasses co-administration of the therapeutic agents in a substantially simultaneous manner, such as in a single dosage unit (eg, capsule) with a fixed ratio of active ingredients or in separate dosage units (eg, capsules) for each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide for the beneficial effects of the drug combination in treating the disorders or conditions described herein.

[0075] "KRAS inhibitor" is used herein to refer to a compound exhibiting an IC50 for KRAS activity of no more than about 100 μM, and more typically no more than about 50 μM, as measured in an assay generally described herein, such as Surface plasmon resonance KRAS-G12D protein binding assay and / or KRAS G12D protein-effector protein interaction disruption assay. "IC50" is the concentration of inhibitor that reduces the activity of an enzyme (eg, KRAS) to half its maximum level. Certain compounds disclosed herein have been found to exhibit inhibition of KRAS. In certain embodiments, the compound will exhibit an IC50 of no more than about 50 μM for KRAS (eg, KRAS with a G12D mutation); in further embodiments, the compound will exhibit no more than about 50 μM for KRAS (eg, KRAS with a G12D mutation). An IC50 of 10 μM; in yet further embodiments, the compound will exhibit an IC50 of no more than about 1 μM for KRAS (eg, KRAS with a G12D mutation); in still further embodiments, the compound for KRAS (eg, KRAS with a G12D mutation) ) will exhibit an IC50 of no more than about 200 nM, as measured in the KRAS assay described herein. In some embodiments, the compound will exhibit less than about 50 μM, such as less than about 40 μM, 30 μM, 20 μM, 10 μM, 5 μM, 1 μM, 500 nM, 200 nM with respect to KRAS (e.g., KRAS with a G12D mutation) , IC50 of 100 nM, 50 nM or less. In certain embodiments, the compound will exhibit an IC50 for KRAS (eg, KRAS with a G12D mutation) of less than about 1 μM. In some embodiments, the KRAS inhibitor is more active against KRAS with a G12D mutation than it is against KRAS with another mutation, such as a G12C, G12R, G12S, G12A, or G12V mutation. For example, in some embodiments, the KRAS inhibitors provided herein have inhibitory activity on KRAS with a G12D mutation relative to KRAS with another mutation, such as a G12C, G12R, G12S, G12A, or G12V mutation, such as a G12C mutation. is at least two times, five times, ten times, twenty times or more. In some embodiments, the KRAS inhibitors provided herein have greater inhibitory activity against active KRAS with a G12D mutation than against inactive KRAS with a G12D mutation. In some embodiments, the KRAS inhibitors provided herein have less inhibitory activity against active KRAS with a G12D mutation than against inactive KRAS with a G12D mutation. In some embodiments, the KRAS inhibitors provided herein have similar inhibitory activity against active and inactive KRAS with a G12D mutation. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against K-RAS4a splice variants. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against K-RAS4b splice variants. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against K-RAS4a and K-RAS4b splice variants.

[0076] "Therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition suitable for treating or ameliorating an identified disease, disorder or disorder or exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see for example Lieberman, Pharmaceutical Dosage Forms (Volumes 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 ed., 2003, Gennaro ed., Lippincott, Williams & Wilkins).

[0077] The term "therapeutically acceptable" means those compounds that are suitable for use in contact with patient tissues without undue toxicity, irritation and allergic response, compatible with a reasonable benefit / risk ratio, and effective for their intended use ( or salts, prodrugs, tautomers, zwitterionic forms, etc.).

[0078] "Treatment", "positive treatment" and "therapy" refer to the treatment or amelioration of any indication of success of an injury, condition or disease, including any objective or subjective parameter such as alleviation; alleviation; reduction of symptoms or reduction of the injury, condition or the disease is more tolerable to the patient; slows the rate of degeneration or decline; makes the final point of degeneration less debilitating; and / or improves the physical or mental health of the patient. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination and / or psychiatric evaluation. Treatment can also be proactive in nature; that is, it can include preventing a disease, disorder or disorder, preventing the onset of one or more symptoms of a disease, disorder or disorder, and / or preventing the escalation of a disease, disorder or disorder. Prevention of a disease, disorder or disorder can involve preventing the disease altogether, and / or preventing disease progression (eg, progression to a later stage of the disease, disorder or disorder). For example, prophylaxis of a disease may not mean the complete exclusion at any level of any effects associated with the disease, but may mean preventing the symptoms of a disease, disorder or disorder to a level that is clinically significant or detectable.

[0079] "Patient" or "individual" refers to a living organism suffering from or susceptible to a disease, disorder or disorder treatable by administration of a compound or pharmaceutical composition as 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-human primates. mammals. Examples of mammals that may 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.), bovines (e.g. cows), odd-toed ungulates (e.g. horses), artiodactyla ungulates (e.g. bovines (such as cattle), ovines (such as sheep ), goats (such as goats), pigs (such as pigs, etc.) and marsupials (such as kangaroos, wallabies, wallabies, sugar gliders, etc.). In some embodiments, the patient or subject is a human. In some embodiments, the patient or individual is a companion animal, such as a cat or dog. In some embodiments, the patient or individual is a farm animal, such as a goat, sheep, cow, pig, or horse. In some embodiments, the patient or individual is an exotic animal such as a primate (e.g. monkey), a marsupial (e.g. kangaroo, wallaby, wallaby, sugar glider, etc.), or a non-domesticated or hybrid cat or dog .

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

[0081] "Pharmaceutically acceptable excipient" means a substance that facilitates administration of an active agent to and absorption by a subject. Pharmaceutical excipients suitable for use in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use in the present disclosure.

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

[0083] The compounds disclosed herein may exist as therapeutically acceptable salts. The disclosure includes compounds provided herein in the form of salts, including acid addition salts. Suitable salts include those formed with organic and inorganic acids. Such acid addition salts will generally be pharmaceutically acceptable. However, salts that are not pharmaceutically acceptable salts may find utility in the preparation and purification of the compounds in question. Basic addition salts may also be formed and are pharmaceutically acceptable.

[0084] As used herein, the term "therapeutically acceptable salt" means a salt or zwitterionic form of a compound disclosed herein which is water-soluble or oil-soluble or dispersible and which is therapeutically acceptable as defined herein. acceptable. Salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in 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), Milk salt, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, Oxalate, Pamoate, Pectate, Persulfate, 3-Phenylpropionate, Phosphonate, Picrate, Pivalate, Propionate, Pyroglutamate, Succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate / p-tosylate) and undecanoate. In addition, basic groups in the compounds disclosed herein can be quaternized with: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl sulfate, Dibutyl sulfate and dipentyl sulfate; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl bromide and phenethyl bromide. Examples of acids which can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric; and organic acids such as oxalic, maleic, succinic, and citric. . Salts can also be formed by coordination of the compounds with alkali metal or alkaline earth ions. Accordingly, this disclosure contemplates the sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0085] Basic addition salts can be obtained 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 amine. , secondary amine or tertiary amine reaction to prepare. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine , triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine (procaine), benzhydrylamine, N,N-benzhydrylphenethylamine, 1-benzhydrylamine (1-ephenamine) and N,N'-benzhydrylethylenediamine. Other representative organic amines suitable for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

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

[0087] "KRAS G12D positive cancer" refers to a cancer characterized by a KRAS G12D mutation.

[0088] As used herein, a "combination therapeutically effective amount" means that the therapeutic agents exhibit (additionally, However, it is preferably a synergistic) interaction (combination therapeutic effect) amount. Whether this is the case can be determined inter alia by following blood levels showing that both compounds are present in the blood of the person to be treated at least during certain time intervals.

[0089] As used herein, "synergy" refers to the action of at least two therapeutic agents: a KRAS G12D inhibitor as defined herein and an additional agent which may be configured to treat a disease, disorder or disorder or its Symptomatic agent. The effect may be, for example, slowing the progression of symptoms of a proliferative disease, such as cancer, especially lung cancer, or a symptom thereof. Similarly, "synergistically effective amount" means the amount required to obtain a synergistic effect

[0090] "A", "an" or "an" when used herein in reference to a set of substituents or a "group of substituents" means at least one. For example, where a compound is substituted with "one" alkyl or aryl, the compound is unsubstituted or substituted with at least one alkyl and / or at least one aryl, wherein each alkyl and / or aryl depends on The situation is different. In another example, where a compound is substituted with "one" set of substituents, the compound is substituted with at least one set of substituents, wherein each set of substituents is optionally different. compound

[0091] In one aspect, the disclosure provides a compound represented by formula I: (I) or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, Zwitterionic forms or stereoisomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring including a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; R2 is selected from From H, 3-6 membered carbocycle and C1-6 alkyl, wherein the 3-6 membered carbocycle or the C1-6 alkyl is unsubstituted or substituted by one or more R13; R3 is selected from C1-6 Alkyl, carbocyclic and heterocyclic, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocyclic or heterocyclic is unsubstituted or substituted by one or more R10; or R2 and R3 are The connected atoms together form a heterocyclic ring which is unsubstituted or substituted by one or more R11; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl Base, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or Multiple R14 substitutions; R5 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring, 3-6 membered heterocyclic ring , 5-6 membered heteroaryl and phenyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and wherein any carbocycle, heterocycle, heteroaryl and phenyl are unsubstituted or Substituted by one or more R14; R6 is phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl, wherein any phenyl, monocyclic heteroaryl, bicyclic aryl and bicyclic heteroaryl are unsubstituted Or substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from H, heterocycle and alkyl heterocycle, wherein the heterocycle or alkyl heterocycle is unsubstituted or Substituted by one or more R16, and wherein the alkyl part of any alkyl heterocycle is selected from C1-6 alkyl; each R9 is independently selected from -N(R17)2, -N(R17)C(O ) C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from halogen, -N(R19)2, -C(O) R19, ​​-C(O)N(R19)2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, - C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N(R19)2,-C(O) R19, ​​-C(O)N(R19)2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, - C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, -OR12, -CN, -N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently is selected from halogen, -OR12, -CN, -N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from Halogen, -N(R12)2, C1-6 alkyl, -OR12 and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected From C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1- 6 alkyl, 3-6 membered heterocycle and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, - CN, -NH2, -NHC1-6 alkyl, halogen and 3-6 membered carbon ring; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

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

[0093] In some embodiments, R1 is -OR8. In some embodiments, R8 is heterocycle. In some embodiments, R8 is an alkyl heterocycle. In some embodiments, R8 is an alkyl heterocycle, wherein the alkyl portion of the alkyl heterocycle is selected from C1-6 alkyl. In some embodiments, R8 is -CH2 (heterocycle). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle comprises 4-8 members including at least one heteroatom selected from N, O, and S (eg, 1-2 heteroatoms). In some embodiments, R8 comprises a heterocycle comprising at least one nitrogen atom. In some embodiments, R8 comprises a 4-8 membered heterocyclic ring including at least one nitrogen atom. In some embodiments, the heterocycle of the heterocycle or alkyl heterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycle or the heterocycle of the alkylheterocycle is an 8-membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is substituted with one or more R16. In some embodiments, at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. In some embodiments, at least one R16 is -OCH3. In some embodiments, at least one R16 is halogen (eg, F). In some embodiments, at least one R16 is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, each R16 is independently selected from halogen, C1-6 alkyl, and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted with one or more R13. In some embodiments, each R16 is independently selected from -F, -CH3, -CH2CH2F, -CH2CHF2, -CH2CH2CN, -OCH3, and -OCHF2.

[0094] In some embodiments, R1 is selected from: wherein Ra and Rb are each independently selected from halogen, C1-6 alkyl, -OR12 and H, wherein any C1-6 alkyl is unsubstituted or through a or multiple R13 substitutions. In some embodiments, Ra is halogen. In some embodiments, Ra is F. In some embodiments, Ra is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra is methyl. In some embodiments, Ra is -OC1-6alkyl. In some embodiments, Ra is H. In some embodiments, Rb is H. In some embodiments, Rb is halogen. In some embodiments, Rb is F. In some embodiments, Rb is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Rb is methyl. In some embodiments, R1 is selected from: , , , and .

[0095] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0096] In some embodiments, R1 is selected from: , , and, wherein each R is independently selected from halogen, C1-6 alkyl, -OR12 and H; and wherein Rc is selected from C1-6 alkyl , wherein the C1-6 alkyl of Ra or Rc is unsubstituted or substituted by one or more R13. In some embodiments, one R is selected from halogen, C1-6 alkyl, and -OR12, and the other R is H. In some embodiments, one Ra is halogen (eg, F). In some embodiments, both Ra are halogen (eg, F). In some embodiments, one Ra is -OR12 (eg, -OCH3 or -CHF2). In some embodiments, one R is C1-6 alkyl (eg, methyl). In some embodiments, two R's are C1-6 alkyl (eg, methyl). In some embodiments, Rc is selected from -CH3, -CH2CH2F, -CH2CHF2, and -CH2CH2CN. In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0097] In some embodiments, R1 is selected from: , , and.

[0098] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,, and.

[0099] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0100] In some embodiments, R1 is a 4-6 membered heterocyclic ring including a nitrogen atom, which is unsubstituted or substituted with one or more R16. In some such embodiments, R16 is selected from -N(R12)2, C1-6 alkyl, and 3-6 membered heterocycle. In some embodiments, R16 is -N(C1-6alkyl)2, such as -N(CH3)2. In some embodiments, R16 is C1-6 alkyl (eg methyl). In some embodiments, R16 is a bicyclic 6-membered heterocycle with 1 nitrogen atom. In some embodiments, R1 is selected from: , , and .

[0101] In some embodiments, R1 is H.

[0102] In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl unsubstituted or substituted with one or more R13. In some such embodiments, each R13 is independently selected from -OR22 (eg, -OH) and -CN. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is selected from -CH3, -CH2CH3, -CH2CH2OH, -CH2CH2CN, and -CH(CH3)2. In some embodiments, R2 is a 3-6 membered carbocyclic ring. In some embodiments, R2 is cyclopropyl.

[0103] In some embodiments, R3 is C1-6 alkyl, which is substituted by one or more R9. In some embodiments, R3 is C1-6 alkyl substituted with -N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2, -NH(CH3) or -N(CH3)2. In some embodiments, R3 is C1-6 alkyl substituted with -N(R17)C(O)C1-6 alkyl (eg, -N(H)C(O)CH3). In some embodiments, R3 is C1-6 alkyl substituted with -OR17 (eg -OH).

[0104] In some embodiments, R3 is selected from: ,,,,,, and.

[0105] In some embodiments, R3 is a carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 4-6 membered carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic carbocycle (eg, a 5-6 membered bicyclic carbocycle). In some embodiments, R3 is monocyclic carbocycle (eg, 4-6 membered monocyclic carbocycle). In some embodiments, R3 is a carbocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is carbocycle substituted with -NH2.

[0106] In some embodiments, R3 is selected from: , and and.

[0107] In some embodiments, R3 is a heterocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic heterocycle (eg, a 6-8 membered bicyclic heterocycle). In some embodiments, R3 is a monocyclic heterocycle (eg, a 4-6 membered monocyclic heterocycle). In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R3 is a heterocycle that is unsubstituted or substituted by one or more R10, wherein each R10 is independently selected from halogen, -N(R19)2, -C(O)R19, -C( O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20 . In some embodiments, R3 is unsubstituted or modified with one or more selected from -F, -CH3, -CH2F, -CH2CN, -C(O)CH3, -C(O)CH2NH2, -C(O) A heterocyclic ring substituted by NH2 and a group. In some embodiments, R3 is a heterocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is heterocycle substituted with -NH2.

[0108] In some embodiments, R3 is selected from the group consisting of: , , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0109] In some embodiments, R3 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0110] In some embodiments, R3 is selected from: ,,,,,,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0111] In some embodiments, R2 or R3 includes an amine moiety (eg, -NRR'). In some embodiments, R2 or R3 is substituted with an amino moiety (ie, -N(R17)2 or -N(R19)2).

[0112] In some embodiments, R2 and R3 together with the atoms to which they are attached (eg nitrogen atom) form a heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together form a 4-9 membered heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur with the atoms to which they are attached (such as a nitrogen atom), wherein the hetero Rings are unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together form a 4-7 membered monocyclic heterocyclic ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen and sulfur with the atoms to which they are attached (such as a nitrogen atom), wherein The heterocycle is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together form a 7-9 membered bicyclic heterocycle with 0-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur with the atoms to which they are attached (such as a nitrogen atom), wherein the The heterocycle is unsubstituted or substituted with one or more R11. In some such embodiments, each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkane group) N(R19)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20. In some embodiments, each R11 is independently selected from -NH2, -NHCH3, -C(O)CH3, -C(O)NH2, -C(O)CH2NH2, -CH3, -CH2CH3, -CH(CH3 )2, -CH2CN, -CH2C(O)NH2, -C(NH)NHCN, -CH2OH and.

[0113] In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocycle selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,, ,,,, and, any of which is unsubstituted or substituted by one or more R11.

[0114] In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,and.

[0115] In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the following structure: ,,,,,,,,,,,,,,,,,,,,,,,, or, Any of them is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a heterocyclic ring having the following structure: ,,,,,,,,,,,,,,,,,,,,,,, Substituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the structure: ,,,,,,, or.

[0116] In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the structure: ,,,, and, any of which is unsubstituted or substituted with one or more R11.

[0117] In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the following structure: ,,,,, or.

[0118] In some embodiments, R2 and R3 together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclic ring comprising additional nitrogen atoms and / or comprising an amine moiety (for example -N(R19)2) group substitution.

[0119] In some embodiments, R4 is H. In some embodiments, R4 is halogen. In some embodiments, R4 is -OR12. In some embodiments, R4 is -OCH3.

[0120] In some embodiments, R5 is a 3-6 membered carbocycle that is unsubstituted or substituted with one or more R14. In some embodiments, R5 is a 3-4 membered carbocycle that is unsubstituted or substituted with one or more R14 (eg, one or more -OR12 or -CN). In some embodiments, R5 is a 3-6 membered heterocyclic ring that is unsubstituted or substituted by one or more R14 (eg, a 3-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) heterocycle). In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety that is unsubstituted or substituted with one or more R14. In some embodiments, R5 is phenyl. In some embodiments, R5 is a 5-6 membered heteroaryl that is unsubstituted or substituted with one or more R14 (eg, C1-6 alkyl). In some embodiments, R5 is pyridyl, furyl or imidazolyl, each unsubstituted or substituted with one or more R14 (eg, C1-6 alkyl). In some embodiments, R5 is furyl.

[0121] In some embodiments, R5 is selected from C1-6 alkyl that is unsubstituted or substituted with one or more R13. In some embodiments, R5 is selected from unsubstituted C1-6 alkyl, such as methyl or ethyl. In some embodiments, R5 is selected from C1-6 alkyl substituted with one or more halogens or -CN. In some embodiments, R5 is selected from -CF3, -CF2H and -CH2CN. In some embodiments, R5 is selected from -CH3, -CH2CH3, -CF2H, -CF3, -CF2CH3, and -CH2CN.

[0122] In some embodiments, R5 is C2-6 alkenyl. In some embodiments, R5 is C2-6 alkynyl (eg, ethynyl).

[0123] In some embodiments, R5 is selected from -OR12, wherein R12 is selected from C1-6 alkyl that is unsubstituted or substituted with one or more R13. In some embodiments, R5 is -OCH3, -OCF3, or -OCF2H.

[0124] In some embodiments, R5 is -CN.

[0125] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F.

[0126] In some embodiments, R5 is hydrogen.

[0127] In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, R7 is -OR12, wherein R12 is selected from H and C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R7 is -OH, -OCH3 or -OCH2CF3. In some embodiments, R7 is -CN. In some embodiments, R7 is hydrogen.

[0128] In some embodiments, R5 and R7 are both halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0129] In some embodiments, R6 is bicyclic aryl or bicyclic heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more R15. In some embodiments, R6 is bicyclic aryl or bicyclic heteroaryl, wherein the aryl or heteroaryl is substituted with one or more R15.

[0130] In some embodiments, R6 is bicyclic aryl substituted with one or more R15. In some embodiments, R6 is naphthyl substituted with one or more R15. In some embodiments, R6 is selected from: , , , and .

[0131] In some embodiments, R6 is a 9-10 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, the heteroaryl is unsubstituted or modified by one or more R15 replaced. In some embodiments, R6 is bicyclic heteroaryl substituted with one or more R15. In some embodiments, R6 is a 9-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with one or more R15. In some such embodiments, at least one R15 is -N(R12)2 (eg, -NH2). In some embodiments, at least one R15 is halogen (eg, F). In some embodiments, each R15 is independently selected from halogen, -CN, and -N(R12)2. In some embodiments, R6 is substituted with at least two R15 (eg, at least one halogen and -NH2).

[0132] In some embodiments, R6 is selected from: ,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R15.

[0133] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,, and.

[0134] In some embodiments, R6 is selected from: ,,,,, and.

[0135] In some embodiments, R6 is: , or.

[0136] In some embodiments, R6 is phenyl or monocyclic heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with one or more R15.

[0137] In some embodiments, R6 is phenyl that is unsubstituted or substituted with one or more R15. In some such embodiments, each R15 is independently selected from halogen, -OR12, -CN, and -N(R12)2. In some embodiments, R6 is selected from: , , , and .

[0138] In some embodiments, R6 is a monocyclic 5-6 membered heteroaryl that is unsubstituted or substituted with one or more R15. In some embodiments, R6 is pyridyl which is unsubstituted or substituted with one or more R15. In some such embodiments, each R15 is independently selected from -N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted with one or more R13. In some embodiments, R6 is.

[0139] In some embodiments, (i) R2 is selected from C1-6 alkyl and 3-6 membered carbocycle, wherein the C1-6 alkyl and 3-6 membered carbocycle are unsubstituted or modified by one or Multiple R13 substitutions; and (ii) R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R10. In some embodiments, R4 is H. In some embodiments, R7 is halogen (eg, F). In some embodiments, R5 is selected from C1-6 alkyl, halogen, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13 , and any carbocyclic and heterocyclic rings are unsubstituted or substituted by one or more R14. In some embodiments, R6 is bicyclic heteroaryl substituted with one or more R15. In some embodiments, R6 is: .

[0140] In some embodiments, R1 is -OR8, wherein R8 is heterocycle or alkylheterocycle. In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0141] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0142] In some embodiments, (i) R2 is selected from C1-6 alkyl (such as methyl or ethyl) that is unsubstituted or substituted by one or more R13; and (ii) R3 is selected from Carbocycle which is unsubstituted or substituted with one or more R10. In some embodiments, (i) R2 is selected from unsubstituted or substituted C1-6 alkyl (such as methyl or ethyl) with one or more R13; and (ii) R3 is selected from unsubstituted Or a heterocyclic ring substituted by one or more R10. In some embodiments, (i) R2 is a 3-6 membered carbocycle (such as cyclopropyl) which is unsubstituted or substituted by one or more R13; and (ii) R3 is selected from unsubstituted or substituted by one or multiple R10 substituted carbocycles. In some embodiments, (i) R2 is a 3-6 membered carbocycle (such as cyclopropyl) which is unsubstituted or substituted by one or more R13; and (ii) R3 is selected from unsubstituted or substituted by one or multiple R10 substituted heterocycles.

[0143] In one aspect, the disclosure provides a compound represented by formula IA: (IA) or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, Zwitterionic forms or stereoisomers wherein R1, R3, R4, R5, R6 and R7 are as defined above for formula I and described herein, individually and in combination, within classes and subclasses. In some embodiments, the disclosure provides a compound of Formula IA or a salt (eg, a pharmaceutically acceptable salt) thereof.

[0144] In some embodiments, the present disclosure provides a compound of formula IA, wherein: R1 is selected from -OR8, a 4-6 membered heterocycle including a nitrogen atom, and H, wherein the heterocycle is unsubstituted or modified by one or A plurality of R16 substitutions; R3 is selected from C1-6 alkyl, carbocyclic and heterocyclic, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocyclic or heterocyclic is unsubstituted or substituted by one Or multiple R10 substitutions; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered hetero Ring, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or modified by one or more R13 is substituted, and any carbocycle and heterocycle are unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, either of which is unsubstituted or substituted by one or more R16, and wherein the alkyl portion of any alkyl heterocycle is selected from C1-6 alkyl ; Each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or through one or more R18 Substitution; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19) 2. -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or through one or more R20 Substitution; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is not Substituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; Each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from From C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1- 6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1 -6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 Alkyl, C2-6 alkenyl and H.

[0145] In some embodiments, R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-6 membered carbocyclic or heterocyclic ring that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-7 membered carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-7 membered heterocycle that is unsubstituted or substituted with one or more R10.

[0146] In some embodiments, R3 is a carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic carbocycle. In some embodiments, R3 is a monocyclic carbocycle. In some embodiments, R3 is a carbocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is carbocycle substituted with -NH2.

[0147] In some embodiments, R3 is a heterocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic heterocycle. In some embodiments, R3 is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R3 is a heterocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is heterocycle substituted with -NH2.

[0148] In some embodiments, R3 is selected from: ,,,,,,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0149] In some embodiments, R3 is selected from: ,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0150] In some embodiments, R3 is selected from: , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0151] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is selected from C1-6 alkyl-N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2.

[0152] In some embodiments, R3 is selected from: , , , , and.

[0153] In some embodiments, R3 includes an amine moiety (eg, -NRR'). In some embodiments, the amine moiety is a component of a heterocycle. In some embodiments, the amine moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amine moiety is a primary amine (eg, -NH2). In some embodiments, the amine moiety is a secondary amine (eg -NHR).

[0154] In some embodiments, R1 is H.

[0155] In some embodiments, R1 is -OR8. In some embodiments, R8 is heterocycle. In some embodiments, R8 is an alkyl heterocycle.

[0156] In some embodiments, R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted with one or more R16. In some embodiments, the heterocycle or heterocycle of an alkylheterocycle comprises 4-8 members including at least one heteroatom selected from N, O, and S. In some embodiments, R8 comprises a heterocycle comprising at least one nitrogen atom. In some embodiments, the heterocycle comprises one or more R16 substituents. In some embodiments, at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. In some embodiments, at least one R16 is -OCH3.

[0157] In some embodiments, R1 is selected from: wherein Ra and Rb are each independently selected from halogen, C1-6 alkyl, -OR12 and H, wherein any C1-6 alkyl is unsubstituted or or multiple R13 substitutions. In some embodiments, Ra is halogen. In some embodiments, Ra is F. In some embodiments, Ra is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra is -OC1-6alkyl. In some embodiments, Ra is H. In some embodiments, Rb is H. In some embodiments, Rb is halogen. In some embodiments, Rb is F. In some embodiments, Rb is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R1 is selected from: , , , and .

[0158] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0159] In some embodiments, R1 is selected from: , , and, wherein each R is independently selected from halogen, C1-6 alkyl, -OR12 and H; and wherein Rc is selected from C1-6 alkyl , wherein the C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0160] In some embodiments, R1 is selected from: , , and.

[0161] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0162] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,,, and.

[0163] In some embodiments, R1 is a 4-6 membered heterocyclic ring including a nitrogen atom, which is unsubstituted or substituted with one or more R16. In some embodiments, R1 is selected from: , and .

[0164] In some embodiments, R6 is selected from: ,,,,,,,,,,,,,, and.

[0165] In some embodiments, R6 is selected from: ,,,,, and.

[0166] In some embodiments, R6 is: , or.

[0167] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0168] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0169] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F. and (ii) R1 is -OR8, wherein R8 is a heterocycle or an alkylheterocycle, wherein the heterocycle or the heterocycle of the alkylheterocycle is a 4-8 membered ring system containing a single nitrogen atom (such as an 8-membered ring system or 5 member ring system). In some embodiments, (iii) R4 is H. In some embodiments, (iv) R7 is halogen. In some embodiments, R3 is selected from the group consisting of: , , , , , , and , any of which is unsubstituted or substituted with one or more R10. In some embodiments, R1 is selected from: wherein each of Ra and Rb is independently selected from halogen, C1-6 alkyl, -OR12 and H. In some embodiments, R1 is selected from: ,,,,,,,, and.

[0171] In some embodiments, R7 is F. In some embodiments, R6 is selected from: ,,,,, and.

[0172] In some embodiments, R5 is selected from -CF3, -Cl, -CH2CN, furan, and phenyl. In some embodiments, (i) R3 is a 4-membered heterocyclic ring (such as azetidine) including a single nitrogen atom, which is unsubstituted or substituted by one or more R10; (ii) R1 is - OR8, wherein R8 is an alkyl heterocycle, wherein the heterocycle is an 8-membered ring system comprising a single nitrogen atom; (iii) R4 is H; and (iv) R7 is halogen. In some embodiments, (i) R3 is a 5-membered heterocyclic ring (such as azetidine) including a single nitrogen atom, which is unsubstituted or substituted by one or more R10; (ii) R1 is - OR8, wherein R8 is an alkyl heterocycle, wherein the heterocycle is an 8-membered ring system comprising a single nitrogen atom; (iii) R4 is H; and (iv) R7 is halogen. and (ii) R1 is -OR8, wherein R8 is a heterocycle or an alkylheterocycle, wherein the heterocycle or the heterocycle of the alkylheterocycle is a 4-8 membered ring system comprising a single nitrogen atom, such as a 5 membered ring system. In some embodiments, (iii) R4 is H. In some embodiments, (iv) R7 is halogen. In some embodiments, R3 is selected from the group consisting of: , , , , , , and , any of which is unsubstituted or substituted with one or more R10. In some embodiments, R1 is selected from: , , and, wherein each Ra is independently selected from halogen, C1-6 alkyl, -OR12, and H; and wherein Rc is selected from C1-6 alkyl, wherein C1-6 alkyl is unsubstituted or substituted with one or more R13. In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0174] In some embodiments, R7 is F. In some embodiments, R6 is selected from: ,,,,, and.

[0175] In some embodiments, R5 is selected from -CF3, -Cl, furan, and phenyl. In some embodiments, (i) R3 is a 4-membered heterocycle comprising a single nitrogen atom (eg, azetidine), which is unsubstituted or substituted with one or more R10; and (ii) R1 is -OR8, wherein R8 is an alkyl heterocycle, wherein the heterocycle is a 5-membered ring system comprising a single nitrogen atom; (iii) R4 is H; and (iv) R7 is halogen. In some embodiments, (i) R3 is a 5-membered heterocycle comprising a single nitrogen atom (eg, pyrrolidine), which is unsubstituted or substituted with one or more R10; and (ii) R1 is -OR8, wherein R8 is an alkyl heterocycle, wherein the heterocycle is a 5-membered ring system comprising a single nitrogen atom; (iii) R4 is H; and (iv) R7 is halogen.

[0176] In some embodiments, (i) R3 is a bridged carbocyclic or heterocyclic ring system that is unsubstituted or substituted with one or more R10; and (ii) R1 is -OR8, wherein R8 is a heterocyclic ring or Alkylheterocycle, wherein the heterocycle or the heterocycle of the alkylheterocycle is a 4-8 membered ring system containing a single nitrogen atom. In some embodiments, (iii) R4 is H. In some embodiments, (iv) R7 is halogen. In some embodiments, (i) R3 is a bridged heterocyclic ring system that is unsubstituted or substituted with one or more R10; and (ii) R1 is -OR8, wherein R8 is a heterocycle or an alkylheterocycle, wherein The heterocycle or heterocycle of an alkylheterocycle is a 4-8 membered ring system containing a single nitrogen atom. In some embodiments, (i) R3 is a bridged carbocyclic ring system that is unsubstituted or substituted with one or more R10; and (ii) R1 is -OR8, wherein R8 is a heterocycle or an alkylheterocycle, wherein The heterocycle or heterocycle of an alkylheterocycle is a 4-8 membered ring system containing a single nitrogen atom. In some embodiments, R3 is selected from: , and .

[0177] In some embodiments, R1 is selected from: , , , and, wherein each Ra and Rb is independently selected from halogen, C1-6 alkyl, -OR12 and H; and wherein Rc is selected from C1- 6 alkyl, wherein the C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments, R1 is selected from: ,,,,,,,, and.

[0178] In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0179] In some embodiments, R7 is F. In some embodiments, R5 is selected from -CF3. In some embodiments, R6 is selected from: ,,,,, and.

[0180] In some embodiments, (i) R3 is a bridged heterocyclic ring system that is unsubstituted or substituted by one or more R10; (ii) R1 is -OR8, wherein R8 is an alkyl heterocycle, wherein A heterocycle is a 4-8 membered ring system comprising a single nitrogen atom; (iii) R4 is H; and (iv) R7 is halogen.

[0181] In some embodiments, (i) R3 is selected from C1-6 alkyl-N(R17)2; and (ii) R1 is -OR8, wherein R8 is an alkyl heterocycle, wherein the heterocycle is A 4-8 membered ring system containing a single nitrogen atom. In some embodiments, (iii) R4 is H. In some embodiments, (iv) R7 is halogen. In some embodiments, R3 is selected from: ,,,, and.

[0182] In some embodiments, (i) R3 is selected from C2 alkyl-N(R17)2; (ii) R1 is -OR8, wherein R8 is an alkyl heterocycle, wherein the heterocycle contains a single nitrogen 4-8 membered ring system of atoms; (iii) R4 is H; and (iv) R7 is halogen. In some embodiments, R6 is: .

[0183] In some embodiments, the disclosure provides compounds according to formula IA1: (IA1) or salts thereof (eg, pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms or stereoisomers wherein R3, R4, R5, R6 and R7 are as defined above for formula I and described individually and in combination within classes and subclasses herein. In some embodiments, the disclosure provides a compound of Formula IAl or a salt (eg, a pharmaceutically acceptable salt) thereof.

[0184] In some embodiments, the disclosure provides compounds according to formula IA1, wherein: R3 is selected from C1-6 alkyl, carbocyclic and heterocyclic, wherein any C1-6 alkyl is replaced by one or more R9 Substituted, and wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2- 6-alkynyl, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle are unsubstituted or substituted One or more R14 substitutions; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R6 is substituted by one or more R15 Bicyclic heteroaryl; R7 is selected from halogen, -OR12, -CN and H; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17 , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19) 2. -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19) 2. -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2 -6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, -N( R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, -N(R12)2 and C1-6 alkyl , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkane Base, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21 ; Each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0185] In some embodiments, R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-6 membered carbocyclic or heterocyclic ring that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-7 membered carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-7 membered heterocycle that is unsubstituted or substituted with one or more R10.

[0186] In some embodiments, R3 is selected from: ,,,,,,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0187] In some embodiments, R3 is selected from: ,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0188] In some embodiments, R3 is selected from: , , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0189] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is selected from C1-6 alkyl-N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2.

[0190] In some embodiments, R3 is selected from: , , , , and.

[0191] In some embodiments, R3 includes an amine moiety (eg, -NRR'). In some embodiments, the amine moiety is a component of a heterocycle. In some embodiments, the amine moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amine moiety is a primary amine (eg, -NH2). In some embodiments, the amine moiety is a secondary amine (eg -NHR).

[0192] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,, and.

[0193] In some embodiments, R6 is selected from: ,,,,, and.

[0194] In some embodiments, R6 is: , or.

[0195] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0196] In some embodiments, R5 is a 3-6 membered carbocyclic ring. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0197] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0198] In some embodiments, the disclosure provides compounds according to Formula IA2: (IA2) or salts thereof (eg, pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms or stereoisomers wherein R3, R4, R5, R6, R7 and R8 are as defined above for formula I and described individually and in combination within classes and subclasses herein. In some embodiments, the disclosure provides a compound of Formula IA2 or a salt thereof (eg, a pharmaceutically acceptable salt).

[0199] In some embodiments, the disclosure provides a compound of formula IA2, wherein: R3 is selected from C1-6 alkyl, carbocyclic and heterocyclic, wherein any C1-6 alkyl is substituted by one or more R9, And wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl Base, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or Multiple R14 substitutions; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered heterocyclic ring, wherein Any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R6 is a bicyclic heterocycle substituted by one or more R15 Aryl; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or substituted by one or more R16; each R9 is independently Selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently Selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1- 6 alkyl) C (O) N (R19) 2, -C (NR19) NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently is selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from- OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or modified by one or more Each R13 is substituted; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected From halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, Wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen ; Each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 Alkenyl and H.

[0200] In some embodiments, R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted with one or more R16.

[0201] In some embodiments, -OR8 is selected from: ,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0202] In some embodiments, -OR8 is selected from: ,,,,,,,, and.

[0203] In some embodiments, R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-6 membered carbocyclic or heterocyclic ring that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is selected from the group consisting of: ,,,,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0204] In some embodiments, R3 is selected from: , , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0205] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is selected from C1-6 alkyl-N(R17)2. In some embodiments, R3 is selected from: ,,,, and.

[0206] In some embodiments, R3 includes an amine moiety (eg, -NRR').

[0207] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,, and.

[0208] In some embodiments, R6 is selected from: ,,,,, and.

[0209] In some embodiments, R6 is: , or.

[0210] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0211] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0212] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0213] In another aspect, the disclosure provides a compound according to formula IB: (IB) or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, a zwitterion Forms or stereoisomers, wherein R1, R4, R5, R6 and R7 are as defined above for formula I and described individually and in combination in classes and subclasses herein; and ring A is unsubstituted or modified by one or Multiple R11 substituted heterocycles. In some embodiments, the disclosure provides a compound of Formula IB or a salt thereof (eg, a pharmaceutically acceptable salt).

[0214] In some embodiments, the disclosure provides a compound of formula IB, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring including a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or modified by one or more R16 is substituted; Ring A is a heterocycle unsubstituted or substituted by one or more R11; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2- 6-alkynyl, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted One or more R14 substitutions; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R6 is substituted by one or more R15 Bicyclic heteroaryl; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or substituted by one or more R16; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1 -6 alkyl) C (O) N (R19) 2, -C (NR19) NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or modified by one or Multiple R13 substitutions; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 Alkyl and halogen; Each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl , C2-6 alkenyl and H.

[0215] In some embodiments, Ring A is a monocyclic heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a polycyclic heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a 4-10 membered heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a 4-6 membered heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A includes at least one nitrogen atom. In some embodiments, Ring A has the following structure: ,,,,,,,,,,,,,,,,,,,,,,,, or, any of which is unsubstituted or modified by one or more R11 replace. In some embodiments, ring A has the following structure: ,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, ring A has the structure: ,,,,,,,, and, the ring is unsubstituted or substituted with one or more R11. In some embodiments, Ring A has the structure: ,,,,, or.

[0216] In some embodiments, Ring A has the following structure: ,,,,,,,,,, and.

[0217] In some embodiments, Ring A is substituted with a group that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or is substituted with a group that includes an amine moiety (eg, -NRR') 4-10 membered heterocycle. In some embodiments, Ring A is 4-6 that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or is substituted with a group that includes an amine moiety (eg, -NRR'). member heterocycle.

[0218] In some embodiments, R1 is H.

[0219] In some embodiments, R1 is -OR8. In some embodiments, R8 is heterocycle. In some embodiments, R8 is an alkyl heterocycle. In some embodiments, the heterocycle or heterocycle of an alkylheterocycle comprises 4-8 members including at least one heteroatom selected from N, O, and S. In some embodiments, R8 comprises a heterocycle comprising at least one nitrogen atom. In some embodiments, R8 comprises a 4-8 membered heterocyclic ring including at least one nitrogen atom. In some embodiments, the heterocycle comprises one or more R16 substituents. In some embodiments, at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. In some embodiments, at least one R16 is -OCH3.

[0220] In some embodiments, R1 is selected from: wherein Ra and Rb are each independently selected from halogen, C1-6 alkyl, -OR12 and H, wherein any C1-6 alkyl is unsubstituted or modified by a or multiple R13 substitutions. In some embodiments, Ra is halogen. In some embodiments, Ra is F. In some embodiments, Ra is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra is -OC1-6alkyl. In some embodiments, Ra is H. In some embodiments, Rb is H. In some embodiments, Rb is halogen. In some embodiments, Rb is F. In some embodiments, Rb is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R1 is selected from: , , , and .

[0221] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0222] In some embodiments, R1 is selected from: , , and, wherein each R is independently selected from halogen, C1-6 alkyl, -OR12 and H; and wherein Rc is selected from C1-6 alkyl , wherein the C1-6 alkyl of Ra or Rc is unsubstituted or substituted by one or more R13. In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0223] In some embodiments, R1 is selected from: , , and.

[0224] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0225] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0226] In some embodiments, R1 is a 4-6 membered heterocyclic ring including a nitrogen atom, which is unsubstituted or substituted with one or more R16. In some embodiments, R1 is selected from: , and .

[0227] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,, and.

[0228] In some embodiments, R6 is selected from the group consisting of: , , , and.

[0229] In some embodiments, R6 is: , or.

[0230] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0231] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0232] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0233] In some embodiments, the disclosure provides compounds according to formula IB1: (IB1) or salts thereof (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms or stereoisomers, wherein R4, R5, R6 and R7 are as defined above for formula I and described individually and in combination in classes and subclasses herein; and ring A is unsubstituted or via one or more R11 Substituted heterocycle. In some embodiments, the disclosure provides a compound of Formula IB1 or a salt (eg, a pharmaceutically acceptable salt) thereof.

[0234] In some embodiments, the disclosure provides a compound of formula IB1, wherein: Ring A is a heterocycle unsubstituted or substituted by one or more R11; R4 is selected from H, halogen, -OR12, -CN , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or via one or more R13 Substituted, and any carbocyclic and heterocyclic rings are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl Base, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or Multiple R14 substitutions; R6 is bicyclic heteroaryl substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; each R11 is independently selected from -N(R19)2, -C (O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O)N(R19) 2. -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 Alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and Halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen , N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R19 is independently selected from C1-6 alkyl and H, wherein any C1 -6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0235] In some embodiments, Ring A is a monocyclic heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a polycyclic heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a 4-10 membered heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a 4-6 membered heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A includes at least one nitrogen atom. In some embodiments, Ring A has the following structure: ,,,,,,,,,,,,,,,,,,,,,,,, or, any of which is unsubstituted or modified by one or more R11 replace. In some embodiments, ring A has the following structure: ,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, ring A has the structure: ,,,,,,,, and, the ring is unsubstituted or substituted with one or more R11. In some embodiments, Ring A has the structure: ,,,,, or.

[0236] In some embodiments, Ring A has the following structure: ,,,,,,,,,, and.

[0237] In some embodiments, Ring A is substituted with a group that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or is substituted with a group that includes an amine moiety (eg, -NRR') 4-10 membered heterocycle. In some embodiments, Ring A is 4-6 that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or is substituted with a group that includes an amine moiety (eg, -NRR'). member heterocycle.

[0238] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,, and.

[0239] In some embodiments, R6 is selected from the group consisting of: , , , , and.

[0240] In some embodiments, R6 is: , or.

[0241] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0242] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0243] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0244] In some embodiments, (i) Ring A is piperazine or diazepane which is unsubstituted or substituted with one or more R11. In some embodiments, (ii) R7 is halogen. In some embodiments, (iii) R4 is H. In some embodiments, Ring A is selected from: and, wherein each Rg is independently selected from H and C1-6 alkyl and Rh is selected from H, C1-6 alkyl, -C(O)NH2, and - C(O)C1-6 alkyl NH2. In some embodiments, at least one Rg is C1-6 alkyl, such as C1 alkyl. In some embodiments, Rh is H. In some embodiments, Ring A is unsubstituted piperazine or diazepane. In some embodiments, Ring A is selected from: and.

[0245] In some embodiments, R7 is F. In some embodiments, R5 is selected from halogen, -CN, C1-6 alkyl and 3-6 membered carbocycle, and the carbocycle or C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments, R6 is: .

[0246] In some embodiments, Ring A is piperazine, which is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a diazepane that is unsubstituted or substituted with one or more R11.

[0247] In some embodiments, (i) Ring A is a bridged heterocyclic ring system that is unsubstituted or substituted with one or more R11. In some embodiments, (ii) R7 is halogen. In some embodiments, (iii) R4 is H. In some embodiments, ring A is selected from: wherein (a) Rg1 and Rg3 or (b) Rg2 and Rg3 are joined together to form a second ring containing 4-6 members, and wherein not as the second ring Any one of a part of Rg1, Rg2, Rg3 and Rg4 is independently selected from H and C1-6 alkyl; and Rh is selected from H, C1-6 alkyl, -C(O)NH2 and -C (O) C1-6 alkyl NH2. In some embodiments, at least one of Rg1, Rg2, Rg3 and Rg4 is C1-6 alkyl, such as C1 alkyl. In some embodiments, Rh is H. In some embodiments, ring A is selected from: wherein Rg2 and Rg4 are joined together to form a second ring containing 4-6 members; Rg1, Rg3 and Rg5 are independently selected from H and C1-6 alkyl; And Rh is selected from H, C1-6 alkyl, -C(O)NH2 and -C(O)C1-6 alkyl NH2. In some embodiments, at least one of Rg1, Rg3 and Rg5 is C1-6 alkyl, such as C1 alkyl. In some embodiments, Rh is H. In some embodiments, Rh is -C(O)NH2. In some embodiments, Ring A is selected from: , , , and .

[0248] In some embodiments, R7 is F. In some embodiments, R5 is selected from halogen, -CN, C1-6 alkyl and 3-6 membered carbocycle, and the carbocycle or C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments, R6 is: .

[0249] In some embodiments, (i) Ring A is a bridged heterocyclic ring system that is unsubstituted or substituted with one or more R11; (ii) R7 is halogen; and (iii) R4 is H.

[0250] In some embodiments, the disclosure provides compounds according to formula IB2: (IB2) or salts thereof (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms or stereoisomers, wherein R4, R5, R6, R7 and R8 are as defined above for formula I and described individually and in combination in classes and subclasses herein; and ring A is unsubstituted or modified by one or more A heterocyclic ring substituted by R11. In some embodiments, the disclosure provides a compound of Formula IB2 or a salt (eg, a pharmaceutically acceptable salt) thereof.

[0251] In some embodiments, the disclosure provides a compound of formula IB2, wherein: Ring A is a heterocycle unsubstituted or substituted by one or more R11; R4 is selected from H, halogen, -OR12, -CN , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or via one or more R13 Substituted, and any carbocyclic and heterocyclic rings are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl Base, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or Multiple R14 substitutions; R6 is bicyclic heteroaryl substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of them Unsubstituted or substituted by one or more R16; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)( C1-6 alkyl) N (R19) 2, - (C1-6 alkyl) C (O) N (R19) 2, - C (NR19) NR19CN and C1-6 alkyl, any C1-6 alkyl Unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or Substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is not Substituted or substituted by one or more R13; Each R13 is substituted; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1 -6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and Halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0252] In some embodiments, Ring A is a monocyclic heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a polycyclic heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a 4-10 membered heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A is a 4-6 membered heterocycle that is unsubstituted or substituted with one or more R11. In some embodiments, Ring A includes at least one nitrogen atom. In some embodiments, Ring A has the following structure: ,,,,,,,,,,,,,,,,,,,,,,,, or, any of which is unsubstituted or modified by one or more R11 replace. In some embodiments, ring A has the following structure: ,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, ring A has the structure: ,,,,,,,, and, the ring is unsubstituted or substituted with one or more R11. In some embodiments, Ring A has the structure: ,,,,, or.

[0253] In some embodiments, Ring A has the following structure: ,,,,,,,,,, and.

[0254] In some embodiments, Ring A is substituted with a group that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or is substituted with a group that includes an amine moiety (eg, -NRR') 4-10 membered heterocycle. In some embodiments, Ring A is 4-6 that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or is substituted with a group that includes an amine moiety (eg, -NRR'). member heterocycle.

[0255] In some embodiments, R8 is heterocycle. In some embodiments, R8 is an alkyl heterocycle. In some embodiments, the heterocycle or heterocycle of an alkylheterocycle comprises 4-8 members including at least one heteroatom selected from N, O, and S. In some embodiments, R8 comprises a heterocycle comprising at least one nitrogen atom. In some embodiments, R8 comprises a 4-8 membered heterocyclic ring including at least one nitrogen atom. In some embodiments, R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted with one or more R16. In some embodiments, the heterocycle comprises one or more R16 substituents. In some embodiments, at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. In some embodiments, at least one R16 is -OCH3.

[0256] In some embodiments, -OR8 is selected from: wherein Ra and Rb are each independently selected from halogen, C1-6 alkyl, -OR12 and H, wherein any C1-6 alkyl is unsubstituted or substituted One or more R13 substitutions. In some embodiments, Ra is halogen. In some embodiments, Ra is F. In some embodiments, Ra is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra is -OC1-6alkyl. In some embodiments, Ra is H. In some embodiments, Rb is H. In some embodiments, Rb is halogen. In some embodiments, Rb is F. In some embodiments, Rb is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, -OR8 is selected from: , , , and .

[0257] In some embodiments, -OR8 is selected from: ,,,,,,,, and.

[0258] In some embodiments, -OR8 is selected from: , , and, wherein each R is independently selected from halogen, C1-6 alkyl, -OR12, and H; and wherein Rc is selected from C1-6 alkane A group, wherein the C1-6 alkyl of Ra or Rc is unsubstituted or substituted by one or more R13. In some embodiments, -OR8 is selected from: ,,,,,,,,,,,, and.

[0259] In some embodiments, -OR8 is selected from: , , and .

[0260] In some embodiments, -OR8 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0261] In some embodiments, -OR8 is selected from: ,,,,,,,, and.

[0262] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,, and.

[0263] In some embodiments, R6 is selected from the group consisting of: , , , , and.

[0264] In some embodiments, R6 is: , or.

[0265] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0266] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0267] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0268] In some embodiments, (i) Ring A is piperazine or diazepane which is unsubstituted or substituted with one or more R11. In some embodiments, (ii) R7 is halogen. In some embodiments, (iii) R4 is H. In some embodiments, Ring A is selected from: and, wherein each Rg is independently selected from H and C1-6 alkyl and Rh is selected from H, C1-6 alkyl, -C(O)NH2, and - C(O)C1-6 alkyl NH2. In some embodiments, at least one Rg is C1-6 alkyl, such as C1 alkyl. In some embodiments, Rh is H. In some embodiments, Ring A is selected from: and.

[0269] In some embodiments, R8 is alkylheterocycle. In some embodiments, -OR8 is selected from: ,,,,,,,, and.

[0270] In some embodiments, -OR8 is selected from: ,,,,,,,,,,,, and.

[0271] In some embodiments, R7 is F. In some embodiments, R5 is selected from halogen, -CN, C1-6 alkyl and 3-6 membered carbocycle, and the carbocycle or C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments, R6 is: .

[0272] In some embodiments, (i) R8 is an alkyl heterocycle; and (ii) Ring A is piperazine, unsubstituted or substituted with one or more R11. In some embodiments, (i) R8 is an alkyl heterocycle; and (ii) Ring A is diazepane, which is unsubstituted or substituted with one or more R11. In some embodiments, (i) R8 is an alkyl heterocycle; and (ii) Ring A is unsubstituted piperazine or diazepane.

[0273] In some embodiments, (i) Ring A is a bridged heterocyclic ring system that is unsubstituted or substituted with one or more R11. In some embodiments, (ii) R7 is halogen. In some embodiments, (iii) R4 is H. In some embodiments, ring A is selected from: wherein (a) Rg1 and Rg3 or (b) Rg2 and Rg3 are joined together to form a second ring containing 4-6 members, and wherein not as the second ring Any one of a part of Rg1, Rg2, Rg3 and Rg4 is independently selected from H and C1-6 alkyl; and Rh is selected from H, C1-6 alkyl, -C(O)NH2 and -C (O) C1-6 alkyl NH2. In some embodiments, at least one of Rg1, Rg2, Rg3 and Rg4 is C1-6 alkyl, such as C1 alkyl. In some embodiments, Rh is H. In some embodiments, ring A is selected from: wherein Rg2 and Rg4 are joined together to form a second ring containing 4-6 members; Rg1, Rg3 and Rg5 are independently selected from H and C1-6 alkyl; And Rh is selected from H, C1-6 alkyl, -C(O)NH2 and -C(O)C1-6 alkyl NH2. In some embodiments, at least one of Rg1, Rg3 and Rg5 is C1-6 alkyl, such as C1 alkyl. In some embodiments, Rh is H. In some embodiments, Rh is -C(O)NH2. In some embodiments, Ring A is selected from: , , , and .

[0274] In some embodiments, R8 is alkylheterocycle. In some embodiments, -OR8 is selected from: ,,,,,,,, and.

[0275] In some embodiments, -OR8 is selected from the group consisting of: ,,,,,,,,,,,, and.

[0276] In some embodiments, R7 is F. In some embodiments, R5 is selected from halogen, -CN, C1-6 alkyl and 3-6 membered carbocycle, and the carbocycle or C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments, R6 is: .

[0277] In some embodiments, (i) R8 is an alkyl heterocycle; (ii) Ring A is a bridged heterocyclic ring system that is unsubstituted or substituted with one or more R11; (iii) R7 is halogen; and (iv) R4 is H.

[0278] In another aspect, the disclosure provides a compound according to formula IC: (IC) or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, a zwitterion Forms or stereoisomers wherein R2, R3, R4, R5, R6 and R7 are as defined above for formula I and described individually and in combination within classes and subclasses herein. In some embodiments, the disclosure provides a compound of Formula IC or a salt thereof (eg, a pharmaceutically acceptable salt).

[0279] In some embodiments, the disclosure provides a compound of formula IC, wherein: R2 is selected from H and C1-6 alkyl; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1 -6 alkyl is substituted by one or more R9, and wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted by one or more R10; or R2 and R3 together form unsubstituted or substituted by one or more R Multiple R11 substituted heterocyclic rings; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 Member heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R5 is selected from halogen, - OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or Or more R13 substitutions, and any carbocyclic and heterocyclic rings are unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; Each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or Or multiple R18 substitutions; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or or multiple R20 substitutions; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or or multiple R20 substitutions; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or via one or more R13 Substitution; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 The alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more Each R13 is substituted; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen ; Each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkane Base, -CN, -NH2, -NHC1-6 alkyl and halogen; Each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and Each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0280] In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is a 3-6 membered carbocyclic ring. In some embodiments, R2 is cyclopropyl.

[0281] In some embodiments, R3 is a carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic carbocycle. In some embodiments, R3 is a monocyclic carbocycle. In some embodiments, R3 is a carbocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is carbocycle substituted with -NH2.

[0282] In some embodiments, R3 is a heterocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic heterocycle. In some embodiments, R3 is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R3 is a heterocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is heterocycle substituted with -NH2.

[0283] In some embodiments, R3 is selected from: ,,,,,,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0284] In some embodiments, R3 is selected from: , , , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0285] In some embodiments, R3 is selected from: , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0286] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is selected from C1-6 alkyl-N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2.

[0287] In some embodiments, R3 is selected from the group consisting of: , , , , and.

[0288] In some embodiments, R3 includes an amine moiety (eg, -NRR'). In some embodiments, the amine moiety is a component of a heterocycle. In some embodiments, the amine moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amine moiety is a primary amine (eg, -NH2). In some embodiments, the amine moiety is a secondary amine (eg -NHR).

[0289] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is C1-6 alkyl substituted with -N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2. In some embodiments, R3 is selected from: ,,,, and.

[0290] In some embodiments, R2 or R3 includes an amine moiety (eg, -NRR').

[0291] In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a monocyclic heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a polycyclic heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a 4-10 membered heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a 4-6 membered heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a structure comprising at least one nitrogen atom. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,,,,,,,,,,,,,,,,,,,, or, any of Unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,, and, the ring is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,, or.

[0292] In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,,, or.

[0293] In some embodiments, R2 and R3 together with the atoms to which they are attached form at least two nitrogen atoms (eg, include an amine moiety (eg -NR-)) and / or include an amine moiety (eg -NRR-) ') group substituted 4-10 membered heterocyclic ring. In some embodiments, R2 and R3 together with the atoms to which they are attached form a compound that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or includes an amine moiety (eg, -NRR'). A 4-6 membered heterocyclic ring substituted by a group.

[0294] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,, and.

[0295] In some embodiments, R6 is selected from the group consisting of: , , , , and.

[0296] In some embodiments, R6 is: , or.

[0297] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0298] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0299] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0300] In another aspect, the disclosure provides compounds according to formula ID or ID': (ID) or (ID') or salts thereof (such as pharmaceutically acceptable salts), esters, tautomers Constructs, prodrugs, zwitterionic forms or stereoisomers, wherein R1, R2, R3, R4, R5 and R7 are as defined above for formula I and described individually and in combination in classes and subclasses herein; R23 is selected from -N(R12)2 and C1-6 alkyl-N(R12)2; and R24, R25 and R26 are independently selected from H, halogen, -OR12 and C1-6 alkyl, wherein any C1- 6 Alkyl is unsubstituted or substituted with one or more R11. In some embodiments, the disclosure provides a compound of Formula ID or a salt (eg, a pharmaceutically acceptable salt) thereof. In some embodiments, the disclosure provides a compound of Formula ID' or a salt (eg, a pharmaceutically acceptable salt) thereof.

[0301] In some embodiments, the present disclosure provides compounds of formula ID or ID', wherein: R is selected from -OR, a 4-6 membered heterocycle including a nitrogen atom, and H, wherein the heterocycle is unsubstituted or Substituted by one or more R16; R2 is selected from H and C1-6 alkyl; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9 , and wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted by one or more R10; or R2 and R3 together form a heterocyclic ring which is unsubstituted or substituted by one or more R11 with the atoms to which they are attached; R4 is selected from From H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered heterocyclic ring, any C1-6 alkyl Unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic rings are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle And the heterocycle is unsubstituted or substituted by one or more R14; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or substituted One or more R16 substitutions; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or Substituted by one or more R18; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkane Base) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or Substituted by one or more R20; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkane Base) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or Substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more Each R13 is substituted; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1 -6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is not Substituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1 -6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH , -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 Alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. R23 is selected from -N(R12)2 and C1-6 alkyl-N(R12)2; and R24, R25 and R26 are independently selected from H, halogen, -OR12 and C1-6 alkyl, wherein any C1 -6 Alkyl is unsubstituted or substituted with one or more R11.

[0302] In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is a 3-6 membered carbocyclic ring. In some embodiments, R2 is cyclopropyl.

[0303] In some embodiments, R3 is a carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic carbocycle. In some embodiments, R3 is a monocyclic carbocycle. In some embodiments, R3 is a carbocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is carbocycle substituted with -NH2.

[0304] In some embodiments, R3 is a heterocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic heterocycle. In some embodiments, R3 is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R3 is a heterocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is heterocycle substituted with -NH2.

[0305] In some embodiments, R3 is selected from: ,,,,,,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0306] In some embodiments, R3 is selected from: , , , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0307] In some embodiments, R3 is selected from: , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0308] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is selected from C1-6 alkyl-N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2.

[0309] In some embodiments, R3 is selected from: , , , , and.

[0310] In some embodiments, R3 includes an amine moiety (eg, -NRR'). In some embodiments, the amine moiety is a component of a heterocycle. In some embodiments, the amine moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amine moiety is a primary amine (eg, -NH2). In some embodiments, the amine moiety is a secondary amine (eg -NHR).

[0311] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is C1-6 alkyl substituted with -N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2. In some embodiments, R3 is selected from: ,,,, and.

[0312] In some embodiments, R2 or R3 includes an amine moiety (eg, -NRR').

[0313] In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a monocyclic heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a polycyclic heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a 4-10 membered heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a 4-6 membered heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a structure comprising at least one nitrogen atom. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,,,,,,,,,,,,,,,,,,,, or, any of Unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,, or.

[0314] In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,,, or.

[0315] In some embodiments, R2 and R3 together with the atoms to which they are attached form at least two nitrogen atoms (eg, include an amine moiety (eg -NR-)) and / or include an amine moiety (eg -NRR-) ') group substituted 4-10 membered heterocyclic ring. In some embodiments, R2 and R3 together with the atoms to which they are attached form a compound that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or includes an amine moiety (eg, -NRR'). A 4-6 membered heterocyclic ring substituted by a group.

[0316] In some embodiments, R1 is H.

[0317] In some embodiments, R1 is -OR8. In some embodiments, R8 is heterocycle. In some embodiments, R8 is an alkyl heterocycle. In some embodiments, the heterocycle or heterocycle of an alkylheterocycle comprises 4-8 members including at least one heteroatom selected from N, O, and S. In some embodiments, R8 comprises a heterocycle comprising at least one nitrogen atom. In some embodiments, R8 comprises a 4-8 membered heterocyclic ring including at least one nitrogen atom. In some embodiments, R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted with one or more R16. In some embodiments, the heterocycle comprises one or more R16 substituents. In some embodiments, at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. In some embodiments, at least one R16 is -OCH3.

[0318] In some embodiments, R1 is selected from: wherein Ra and Rb are each independently selected from halogen, C1-6 alkyl, -OR12 and H, wherein any C1-6 alkyl is unsubstituted or modified by a or multiple R13 substitutions. In some embodiments, Ra is halogen. In some embodiments, Ra is F. In some embodiments, Ra is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra is -OC1-6alkyl. In some embodiments, Ra is H. In some embodiments, Rb is H. In some embodiments, Rb is halogen. In some embodiments, Rb is F. In some embodiments, Rb is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R1 is selected from: , , , and .

[0319] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,, and.

[0320] In some embodiments, R1 is selected from: , , and, wherein each R is independently selected from halogen, C1-6 alkyl, -OR12 and H; and wherein Rc is selected from C1-6 alkyl , wherein the C1-6 alkyl of Ra or Rc is unsubstituted or substituted by one or more R13. In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0321] In some embodiments, R1 is selected from: , , and.

[0322] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0323] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0324] In some embodiments, R1 is a 4-6 membered heterocyclic ring including a nitrogen atom, which is unsubstituted or substituted with one or more R16. In some embodiments, R1 is selected from: , and .

[0325] In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0326] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0327] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0328] In some embodiments, R23 is -N(R12)2. In some embodiments, R23 is -NH2.

[0329] In some embodiments, R24 is halogen. In some embodiments, R24 is Cl or F. In some embodiments, R24 is F. In some embodiments, R24 is H.

[0330] In some embodiments, R25 and R26 are H. In some embodiments, R25 is H. In some embodiments, R26 is H.

[0331] In one aspect, the disclosure provides a compound represented by formula IE: (IE) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, Zwitterionic forms or stereoisomers wherein R2, R3, R4, R5, R6 and R7 are as defined above for formula I and described individually and in combination within classes and subclasses herein; and Ra and Rb are independently selected from halogen, -OR12, C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments, the disclosure provides a compound of Formula IE or a salt thereof (eg, a pharmaceutically acceptable salt).

[0332] In some embodiments, the disclosure provides a compound of formula IE, wherein: R2 is selected from H, 3-6 membered carbocycle and C1-6 alkyl, wherein the 3-6 membered carbocycle or the C1- 6 alkyl is unsubstituted or substituted by one or more R13; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbon The ring or heterocyclic ring is unsubstituted or substituted by one or more R10; or R2 and R3 form a heterocyclic ring which is unsubstituted or substituted by one or more R11 together with the atoms they are connected to; R4 is H, halogen, -OR12 , -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or modified by one or Multiple R13 substitutions, and any carbocyclic and heterocyclic rings are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2 -6 alkynyl, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle are unsubstituted or Substituted by one or more R14; R6 is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; each R9 is independently selected from -N(R17)2 , -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N(R19) 2. -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O) N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N(R19) 2. -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O) N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl , C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N( R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently is selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H ; Each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H; and Ra and Rb are independently selected from halogen, -OR12, C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13.

[0333] In some embodiments, Ra is halogen. In some embodiments, Ra is F. In some embodiments, Ra is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra is -OC1-6alkyl. In some embodiments, Ra is H. In some embodiments, Rb is H. In some embodiments, Rb is halogen. In some embodiments, Rb is F. In some embodiments, Rb is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra and Rb are both halogen. In some embodiments, both Ra and Rb are F. In some embodiments, both Ra and Rb are C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra and Rb are both methyl. In some embodiments, Ra and Rb are both H. In some embodiments, Ra is -OC1-6alkyl and Rb is H.

[0334] In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is a 3-6 membered carbocyclic ring. In some embodiments, R2 is cyclopropyl.

[0335] In some embodiments, R3 is C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is C1-6 alkyl substituted with -N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H. In some embodiments, R3 is C1-6 alkyl substituted with -NH2.

[0336] In some embodiments, R3 is selected from the group consisting of: , , , , and.

[0337] In some embodiments, R3 includes an amine moiety (eg, -NRR'). In some embodiments, the amine moiety is a component of a heterocycle. In some embodiments, the amine moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amine moiety is a primary amine (eg, -NH2). In some embodiments, the amine moiety is a secondary amine (eg -NHR).

[0338] In some embodiments, R3 is a carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic carbocycle. In some embodiments, R3 is a monocyclic carbocycle. In some embodiments, R3 is a carbocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is carbocycle substituted with -NH2.

[0339] In some embodiments, R3 is a heterocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a polycyclic heterocycle. In some embodiments, R3 is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R3 is a heterocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is heterocycle substituted with -NH2. In some embodiments, R3 is a bridged heterocyclic ring system. In some embodiments, R3 is a monocyclic ring. In some embodiments, R3 is azetidine or pyrrolidine which is unsubstituted or substituted with one or more R10.

[0340] In some embodiments, R3 is selected from: ,,,,,,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10.

[0341] In some embodiments, R3 is selected from: , , , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0342] In some embodiments, R3 is selected from: , , , , , and, any of which is unsubstituted or substituted with one or more R10.

[0343] In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a monocyclic heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a polycyclic heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a 4-10 membered heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a 4-6 membered heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a structure comprising at least one nitrogen atom. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,,,,,,,,,,,,,,,,,, any of which is not Substituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,,,,, or, the ring is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a ring having the following structure: ,,,,, or.

[0344] In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a heterocyclic ring having the following structure: ,,,,,,,,, or.

[0345] In some embodiments, R2 and R3 together with the atoms to which they are attached form at least two nitrogen atoms (eg, include an amine moiety (eg -NR-)) and / or include an amine moiety (eg -NRR-) ') group substituted 4-10 membered heterocyclic ring. In some embodiments, R2 and R3 together with the atoms to which they are attached form a compound that includes at least two nitrogen atoms (eg, includes an amine moiety (eg, -NR-)) and / or includes an amine moiety (eg, -NRR'). A 4-6 membered heterocyclic ring substituted by a group.

[0346] In some embodiments, R4 is H. In some embodiments, R4 is halogen. In some embodiments, R4 is -OR12. In some embodiments, R4 is -OCH3.

[0347] In some embodiments, R5 is a 3-6 membered carbocyclic ring. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0348] In some embodiments, R5 is selected from C1-6 alkyl that is unsubstituted or substituted with one or more R13. In some embodiments, R5 is selected from unsubstituted C1-6 alkyl, such as methyl or ethyl. In some embodiments, R5 is selected from C1-6 alkyl substituted with one or more halogens or -CN. In some embodiments, R5 is selected from -CF3, -CF2H and -CH2CN. In some embodiments, R5 is selected from -OR12, wherein R12 is selected from C1-6 alkyl that is unsubstituted or substituted with one or more R13. In some embodiments, R5 is -OCH3, -OCF3, or -OCF2H.

[0349] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0350] In some embodiments, R6 is bicyclic aryl substituted with one or more R15. In some embodiments, R6 is selected from: , , and .

[0351] In some embodiments, R6 is bicyclic heteroaryl substituted with one or more R15. In some embodiments, R6 is selected from: ,,,,,,,,,,,,,, and.

[0352] In some embodiments, R6 is selected from the group consisting of: , , , , and.

[0353] In some embodiments, R6 is selected from: , or .

[0354] In some embodiments, (i) R6 is a bicyclic heteroaryl substituted by one or more R15, and (ii) R2 and R3 together with the atom to which they are attached (such as a nitrogen atom) form an unsubstituted or A heterocyclic ring substituted by one or more R11. In some embodiments, R6 is selected from: ,,,,, and.

[0355] In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a heterocyclic ring having the following structure: ,,,,,,,,,,,,,,,,,,,,,,,, , , or, any of which is unsubstituted or substituted by one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the structure: ,,,, or, any of which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the structure: ,,,,, or.

[0356] In some embodiments, R4 is H. In some embodiments, R7 is halogen (eg, F). In some embodiments, (i) R6 is a bicyclic heteroaryl substituted by one or more R15, and (ii) R2 and R3 together form the atom to which they are attached (such as a nitrogen atom) to form unsubstituted or substituted by one or more Bridged heterocyclic ring system with multiple R11 substitutions. In some embodiments, (i) R6 is a bicyclic heteroaryl substituted with one or more R15, and (ii) R2 and R3 together with the atoms to which they are attached (eg nitrogen atom) form a bridge comprising a piperazine ring A heterocyclic ring system, the bridged heterocyclic ring system is unsubstituted or substituted with one or more R11. In some embodiments, (i) R6 is a bicyclic heteroaryl substituted by one or more R15, and (ii) R2 and R3 together form the atom to which they are attached (such as a nitrogen atom) to form unsubstituted or substituted by one or more Multiple R11 substituted piperazine rings.

[0357] In some embodiments, (i) R6 is a bicyclic heteroaryl substituted by one or more R15; (ii) R2 is selected from H, C1-6 alkyl and 3-6 membered carbocycles, wherein The C1-6 alkyl or 3-6 membered carbon ring is unsubstituted or substituted by one or more R13; and (iii) R3 is C1-6 alkyl, the C1-6 alkyl is substituted by one or more R9 . In some embodiments, R3 is C1-6 alkyl substituted with -NH2. In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R2 is a 3-6 membered carbocycle that is unsubstituted or substituted with one or more R13.

[0358] In some embodiments, (i) R6 is a bicyclic heteroaryl substituted by one or more R15; (ii) R2 is selected from H, C1-6 alkyl and 3-6 membered carbocycles, wherein The C1-6 alkyl or 3-6 membered carbocycle is unsubstituted or substituted by one or more R13; and (iii) R3 is a carbocycle which is unsubstituted or substituted by one or more R10. In some embodiments, R3 is cyclobutyl unsubstituted or substituted with one or more R10. In some embodiments, R3 is a carbocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is carbocycle substituted with -NH2. In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R2 is a 3-6 membered carbocycle that is unsubstituted or substituted with one or more R13.

[0359] In some embodiments, (i) R6 is a bicyclic heteroaryl substituted by one or more R15; (ii) R2 is selected from H, C1-6 alkyl and 3-6 membered carbocycles, wherein The C1-6 alkyl or 3-6 membered carbocycle is unsubstituted or substituted by one or more R13; and (iii) R3 is a heterocycle, which is unsubstituted or substituted by one or more R10. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R3 is a heterocycle substituted with -N(R19)2, wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H. In some embodiments, R3 is heterocycle substituted with -NH2. In some embodiments, R3 is a bridged heterocyclic ring system. In some embodiments, R3 is a monocyclic ring. In some embodiments, R3 is azetidine or pyrrolidine which is unsubstituted or substituted with one or more R10. In some embodiments, R3 is selected from: ,,,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R10. In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R2 is a 3-6 membered carbocycle that is unsubstituted or substituted with one or more R13.

[0360] In one aspect, the disclosure provides a compound represented by formula IF: (IF) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, Zwitterionic forms or stereoisomers wherein R1, R4, R5, R6 and R7 are as defined above for formula I and described individually and in combination in classes and subclasses herein; Rg1, Rg2, Rg3 and Rg4 are each independently selected from H and C1-6 alkyl; or (a) Rg1 and Rg3 or (b) Rg2 and Rg3 linked together to form a second ring containing 4-6 members, and not being part of the second ring Any one of Rg1, Rg2, Rg3 and Rg4 is independently selected from H and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; and Rh is selected from H , C1-6 alkyl, -C(O)NH2 and -C(O)C1-6 alkyl NH2. In some embodiments, the disclosure provides a compound of Formula IF or a salt (eg, a pharmaceutically acceptable salt) thereof.

[0361] In some embodiments, the present disclosure provides a compound of formula IF, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring including a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or modified by one or Multiple R16 substitutions; Rg1, Rg2, Rg3 and Rg4 are each independently selected from H and C1-6 alkyl; or (a) Rg1 and Rg3 or (b) Rg2 and Rg3 are linked together to form a group containing 4-6 members The second ring, and any of Rg1, Rg2, Rg3, and Rg4 that are not part of the second ring are independently selected from H and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or Substituted by one or more R13; Rh is selected from H, C1-6 alkyl, -C (O) NH2 and -C (O) C1-6 alkyl NH2; R4 is selected from H, halogen, -OR12, - CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or modified by one or more R13 is substituted, and any carbocycle and heterocycle are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2- 6-alkynyl, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted One or more R14 substitutions; R6 is a bicyclic heteroaryl substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; each R12 is independently selected from C1-6 alkyl, C2 - 6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22) 2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; and each R22 is independently selected from C1-6 alkyl, C2- 6 alkenyl and H.

[0362] In some embodiments, R1 is -OR8. In some embodiments, R8 is heterocycle. In some embodiments, R8 is an alkyl heterocycle. In some embodiments, the heterocycle or heterocycle of an alkylheterocycle comprises 4-8 members including at least one heteroatom selected from N, O, and S. In some embodiments, R8 comprises a heterocycle comprising at least one nitrogen atom. In some embodiments, R8 comprises a 4-8 membered heterocyclic ring including at least one nitrogen atom. In some embodiments, the heterocycle comprises one or more R16 substituents. In some embodiments, at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. In some embodiments, at least one R16 is -OCH3.

[0363] In some embodiments, R1 is selected from: wherein Ra and Rb are each independently selected from halogen, C1-6 alkyl, -OR12 and H. In some embodiments, Ra and Rb are each independently selected from halogen, C1-6 alkyl, -OR12 and H, wherein any C1-6 alkyl is unsubstituted or substituted with one or more R13. In some embodiments, Ra is halogen. In some embodiments, Ra is F. In some embodiments, Ra is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, Ra is -OC1-6alkyl. In some embodiments, Ra is H. In some embodiments, Rb is H. In some embodiments, Rb is halogen. In some embodiments, Rb is F. In some embodiments, Rb is C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R1 is selected from: , , , and .

[0364] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0365] In some embodiments, R1 is selected from: , , and, wherein each R is independently selected from halogen, C1-6 alkyl, -OR12, and H; and wherein R is selected from C1-6 alkyl , wherein the C1-6 alkyl of Ra or Rc is unsubstituted or substituted by one or more R13. In some embodiments, R1 is selected from: ,,,,,,,,,,,,, and.

[0366] In some embodiments, R1 is selected from: , , and.

[0367] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0368] In some embodiments, R1 is selected from: ,,,,,,,, and.

[0369] In some embodiments, R1 is a 4-6 membered heterocyclic ring including a nitrogen atom, which is unsubstituted or substituted with one or more R16. In some embodiments, R1 is selected from: , and .

[0370] In some embodiments, R1 is H.

[0371] In some embodiments, R4 is H. In some embodiments, R4 is halogen. In some embodiments, R4 is -OR12. In some embodiments, R4 is -OCH3.

[0372] In some embodiments, R5 is a 3-6 membered carbocycle. In some embodiments, R5 is a 3-6 membered heterocycle. In some embodiments, R5 is a 5 or 6 membered aryl or heteroaryl moiety. In some embodiments, R5 is furan.

[0373] In some embodiments, R5 is selected from C1-6 alkyl that is unsubstituted or substituted with one or more R13. In some embodiments, R5 is selected from unsubstituted C1-6 alkyl, such as methyl or ethyl. In some embodiments, R5 is selected from C1-6 alkyl substituted with one or more halogens or -CN. In some embodiments, R5 is selected from -CF3, -CF2H and -CH2CN. In some embodiments, R5 is selected from -OR12, wherein R12 is selected from C1-6 alkyl that is unsubstituted or substituted with one or more R13. In some embodiments, R5 is -OCH3, -OCF3, or -OCF2H.

[0374] In some embodiments, R5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, both R5 and R7 are halogen. In some embodiments, both R5 and R7 are selected from Cl and F. In some embodiments, R4, R5, and R7 are each independently halogen. In some embodiments, R4, R5 and R7 are each selected from Cl and F.

[0375] In some embodiments, R6 is bicyclic aryl substituted with one or more R15. In some embodiments, R6 is selected from: , , and .

[0376] In some embodiments, R6 is bicyclic heteroaryl substituted with one or more R15. In some embodiments, R6 is selected from: ,,,,,,,,,,,,,, and.

[0377] In some embodiments, R6 is selected from the group consisting of: , , , , and.

[0378] In some embodiments, R6 is selected from: , or .

[0379] In some embodiments, Rg1 is selected from C1-6 alkyl (eg, methyl). In some embodiments, Rg2 is selected from C1-6 alkyl (eg methyl). In some embodiments, Rg3 is selected from C1-6 alkyl (eg methyl). In some embodiments, Rg4 is selected from C1-6 alkyl (eg methyl). In some embodiments, Rg1 and Rg2 are selected from C1-6 alkyl (such as methyl). In some embodiments, Rg1 and Rg2 are both methyl groups. In some embodiments, Rg1 and Rg3 are selected from C1-6 alkyl (such as methyl). In some embodiments, both Rg1 and Rg3 are methyl. In some embodiments, Rg1 and Rg4 are selected from C1-6 alkyl (such as methyl). In some embodiments, both Rg1 and Rg4 are methyl. In some embodiments, Rg2 and Rg3 are selected from C1-6 alkyl (such as methyl). In some embodiments, both Rg2 and Rg3 are methyl.

[0380] In some embodiments, Rg1 and Rg3 are linked together to form a second loop containing 4-6 members. In some embodiments, Rg2 and Rg3 are joined together to form a second loop containing 4-6 members. In some embodiments, Rh is H.

[0381] In some embodiments, the compound has the following structure: (IF1), (IF2), (IF3) or (IF4).

[0382] In some embodiments of compounds according to Formula (IF1) or (IF2), Rg1 and Rg4 are each H. In some embodiments of compounds according to Formula (IF3) or (IF4), Rg2 and Rg4 are each H. In some embodiments of compounds according to Formula (IF1), (IF2), (IF3) or (IF4), Rh is H. In some embodiments of compounds according to formula (IF1), (IF2), (IF3) or (IF4), R1 is selected from: wherein Ra and Rb are each independently selected from halogen, C1-6 alkyl, - OR12 and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13. In some embodiments of compounds according to formula (IF1), (IF2), (IF3) or (IF4), R6 is selected from: ,,,,, and.

[0383] In some embodiments of compounds according to Formula (IF1), (IF2), (IF3) or (IF4), R4 is H. In some embodiments of compounds according to Formula (IF1), (IF2), (IF3) or (IF4), R7 is halogen (eg, F). In some embodiments of compounds according to formula (IF1), (IF2), (IF3) or (IF4), R5 is halogen, -CN, 3-6 membered carbocycle, 3-6 membered heterocycle, or C1-6 alkyl substituted or substituted by one or more R13.

[0384] In another aspect, the disclosure provides a compound according to formula II: (II) or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, a zwitterion Forms or stereoisomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring including a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; R2 is selected from H , 3-6 membered carbocycle and C1-6 alkyl, wherein the 3-6 membered carbocycle or the C1-6 alkyl is unsubstituted or substituted by one or more R13; R3 is selected from C1-6 alkyl , carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10; or R2 and R3 are attached to The atoms together form an unsubstituted or substituted heterocyclic ring with one or more R11; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or more R14 is substituted; R6 is phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl, wherein any phenyl, monocyclic heteroaryl, bicyclic aryl and bicyclic heteroaryl are unsubstituted or modified by one or more R15 is substituted; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from H, heterocycle and alkyl heterocycle, wherein the heterocycle or alkyl heterocycle is unsubstituted or through one or more R16 is substituted, and the alkyl part of any alkyl heterocycle is selected from C1-6 alkyl; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkane and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from halogen, -N(R19)2, -C(O)R19, -C( O )N(R19)2, -C(O)(C1-6alkyl)N(R19)2, -(C1-6alkyl)C(O)N(R19)2, -C(NR19)NR19CN And C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N(R19)2, -C(O)R19, -C( O )N(R19)2, -C(O)(C1-6alkyl)N(R19)2, -(C1-6alkyl)C(O)N(R19)2, -C(NR19)NR19CN And C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1 -6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from from halogen, -OR12, -CN, -N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, - OR12, -CN, -N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N( R12) 2, C1-6 alkyl, -OR12 and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkane and H; Each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl, 3 - 6-membered heterocycle and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, - NHC1-6 alkyl, halogen and 3-6 membered carbon ring; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

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

[0386] In some embodiments, the present disclosure provides a compound of formula II, wherein: R1 is selected from -OR8, a 4-6 membered heterocycle including a nitrogen atom, and H, wherein the heterocycle is unsubstituted or modified by one or more R16 is substituted; R2 is selected from H and C1-6 alkyl; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the Carbocycle or heterocycle is unsubstituted or substituted by one or more R10; or R2 and R3 form a heterocycle unsubstituted or substituted by one or more R11 together with the atoms they are connected to; R4 is selected from H, halogen , -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or Substituted by one or more R13, and any carbocycle and heterocycle are unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, - OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or substituted by one or more R16; each R9 is independently selected from -N(R17)2, - N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N( R19) 2, -C (NR19) NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N (R19) 2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N( R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2 -6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22) 2 and halogen; each R14 is independently selected from halogen, -OR12, -CN, -N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13 ; Each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; Each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1 -6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0387] In some embodiments, R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 3-6 membered carbocyclic or heterocyclic ring that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 4-6 membered carbocycle that is unsubstituted or substituted with one or more R10. In some embodiments, R3 is a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is unsubstituted or substituted with one or more R10. In some embodiments, R3 is azetidine which is unsubstituted or substituted with one or more R10. In some embodiments, R3 is selected from: , , , , , , , and , any of which is unsubstituted or substituted with one or more R10.

[0388] In some embodiments, R3 is selected from C1-6 alkyl substituted with one or more R9. In some embodiments, R3 is selected from C1-6 alkyl-N(R17)2. In some embodiments, R3 is -CH2CH2NH2. In some embodiments, R3 is selected from: ,,,, and.

[0389] In some embodiments, R2 or R3 includes an amine moiety (eg, -NRR'). In some embodiments, R2 or R3 is substituted with an amino moiety (ie, -N(R17)2 or -N(R19)2).

[0390] In some embodiments, R2 and R3 are taken together with the atoms to which they are attached to form a 4-6 membered heterocyclic ring which is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together form a 4-9 membered heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur with the atoms to which they are attached (such as a nitrogen atom), wherein the hetero Rings are unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together form a 4-7 membered monocyclic heterocyclic ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen and sulfur with the atoms to which they are attached (such as a nitrogen atom), wherein The heterocycle is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together with the atom to which they are attached (eg nitrogen atom) form piperazine. In some embodiments, R2 and R3 together form a 7-9 membered bicyclic heterocycle with 0-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur with the atoms to which they are attached (such as a nitrogen atom), wherein the The heterocycle is unsubstituted or substituted with one or more R11. In some embodiments, R2 and R3 together form a heterocyclic ring with the following structure: ,,,,,,,,,,,,, or, the ring is unsubstituted or substituted by one or more R11 . In some embodiments, R2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the structure: ,,,,,,,,,, or.

[0391] In some embodiments, R2 and R3 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocyclic ring comprising additional nitrogen atoms (e.g., an amino moiety such as - NR-)) and / or substituted with a group including an amine moiety (eg -N(R19)2).

[0392] In some embodiments, R1 is H.

[0393] In some embodiments, R1 is -OR8. In some embodiments, R1 is -OR8, wherein R8 is heterocycle or alkylheterocycle. In some embodiments, R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted with one or more R14. In some embodiments, R8 is heterocycle. In some embodiments, R8 is an alkyl heterocycle. In some embodiments, R8 is an alkyl heterocycle, wherein the alkyl portion of the alkyl heterocycle is selected from C1-6 alkyl. In some embodiments, R8 is -CH2 (heterocycle). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle comprises 4-8 members including at least one heteroatom selected from N, O, and S. In some embodiments, R8 comprises a heterocycle comprising at least one nitrogen atom. In some embodiments, R8 comprises a 4-8 membered heterocyclic ring including at least one nitrogen atom. In some embodiments, the heterocycle or the heterocycle of the alkyl heterocycle is a 4-6 monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle or the heterocycle of the alkylheterocycle is an 8-membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is substituted with one or more R16. In some embodiments, at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. In some embodiments, at least one R16 is -OCH3. In some embodiments, at least one R16 is halogen (eg, F). In some embodiments, at least one R16 is C1-6 alkyl unsubstituted or substituted with one or more R13.

[0394] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,,,,,,, and.

[0395] In some embodiments, R1 is selected from the group consisting of: ,,,,,,,,,,,,,,, and.

[0396] In some embodiments, R1 is a 4-6 membered heterocyclic ring including a nitrogen atom, which is unsubstituted or substituted with one or more R16. In some such embodiments, R16 is selected from -N(R12)2, C1-6 alkyl, and 3-6 membered heterocycle. In some embodiments, R16 is -N(C1-6alkyl)2, such as -N(CH3)2. In some embodiments, R16 is C1-6 alkyl (eg methyl). In some embodiments, R16 is a bicyclic 6-membered heterocycle with 1 nitrogen atom. In some embodiments, R1 is selected from: , and .

[0397] In some embodiments, R6 is bicyclic aryl substituted with one or more R15. In some embodiments, R6 is naphthyl substituted with one or more R15.

[0398] In some embodiments, R6 is a 9-10 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is unsubstituted or modified by one or more R15 replaced. In some embodiments, R6 is bicyclic heteroaryl substituted with one or more R15. In some embodiments, R6 is a 9-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with one or more R15. In some such embodiments, at least one R15 is -N(R12)2 (eg, -NH2). In some embodiments, at least one R15 is halogen (eg, F). In some embodiments, each R15 is independently selected from halogen, -CN, and -N(R12)2. In some embodiments, R6 is substituted with at least two R15 (eg, at least one halogen and -NH2).

[0399] In some embodiments, R6 is selected from: ,,,,,,,,, and, any of which is unsubstituted or substituted with one or more R15.

[0400] In some embodiments, R6 is selected from the group consisting of: ,,,,,,,,,,,,,,,,,,,,, and.

[0401] In some embodiments, R6 is selected from: ,,,,, and.

[0402] In some embodiments, R6 is: , or.

[0403] In some embodiments, R6 is phenyl which is unsubstituted or substituted with one or more R15. In some such embodiments, each R15 is independently selected from halogen, -OR12, -CN, and -N(R12)2.

[0404] In some embodiments, R6 is a monocyclic 5-6 membered heteroaryl that is unsubstituted or substituted with one or more R15. In some embodiments, R6 is pyridyl which is unsubstituted or substituted with one or more R15. In some such embodiments, each R15 is independently selected from -N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted with one or more R13.

[0405] In some embodiments, R4 is H. In some embodiments, R4 is halogen. In some embodiments, R4 is -OR12. In some embodiments, R4 is -OCH3.

[0406] In some embodiments, R7 is halogen. In some embodiments, R7 is Cl or F. In some embodiments, R7 is -OR12, wherein R12 is selected from H and C1-6 alkyl unsubstituted or substituted with one or more R13. In some embodiments, R7 is -OH, -OCH3 or -OCH2CF3. In some embodiments, R7 is -CN. In some embodiments, R7 is hydrogen.

[0407] In some embodiments, R4 and R7 are both halogen. In some embodiments, both R4 and R7 are selected from Cl and F.

[0408] In some embodiments, the compound is represented by a formula included in any one of Tables 2-9. In some embodiments, the present disclosure provides a compound selected from any one of Table 2, Table 3, Table 4, Table 5, Table 7, Table 8, and Table 9 or a salt thereof (such as a pharmaceutically acceptable Salt). In some embodiments, the disclosure provides a compound selected from any one of Table 2, Table 3, Table 4, Table 7, Table 8, and Table 9, or a salt thereof (eg, a pharmaceutically acceptable salt thereof). Also provided herein is a compound selected from any one of Tables 2 to 9 or any one of the Examples provided herein, or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof Construct. It is to be understood that the compounds described herein may be provided and / or utilized in any useful form (eg, salt form) and that this disclosure contemplates all such forms. This disclosure also contemplates forms of the compounds provided herein, such as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers.

[0410] In some embodiments, provided compounds are provided and / or utilized in salt form (eg, a pharmaceutically acceptable salt form). Unless otherwise indicated, reference to a compound provided herein is to be understood as including reference to a salt thereof.

[0411] Also provided herein are embodiments in which any of the embodiments described herein can be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive. As used herein, two embodiments are "mutually exclusive" when one embodiment is defined as being different from the other. For example, embodiments where two groups combine to form a ring are mutually exclusive to embodiments where one group is ethyl and the other is hydrogen. Similarly, embodiments where one group is CH2 are mutually exclusive to embodiments where the same group is NH. combination

[0412] The disclosure also provides a composition (e.g., a pharmaceutical composition) comprising a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID ', IE, IF or II) or salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers thereof. In some embodiments, provided compositions comprise a compound provided herein, or a pharmaceutically acceptable salt thereof. For example, the disclosure provides a pharmaceutical composition comprising a compound provided herein (e.g., Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, A compound of any one of IF or II) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof, and a pharmaceutically acceptable carrier. In some embodiments, provided pharmaceutical compositions comprise a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0413] In some embodiments, pharmaceutical compositions are formulated for oral administration. In some embodiments, the oral pharmaceutical formulation is selected from tablets and capsules.

[0414] In some embodiments, pharmaceutical compositions are formulated for parenteral administration. In some embodiments, pharmaceutical compositions are formulated for intravenous administration. In some embodiments, pharmaceutical compositions are formulated for subcutaneous administration.

[0415] Although certain compounds provided herein (such as compounds of any one of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II) or salts thereof , esters, tautomers, prodrugs, zwitterionic forms or stereoisomers may be administered as the original chemical, but the compound may additionally or alternatively be provided in a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations comprising one or more compounds disclosed herein (e.g., Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF , or any compound in II) or one or more pharmaceutically acceptable salts, esters, prodrugs, amides or solvates thereof, and one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent on the chosen route of administration. 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 known suitable manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0416] 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 transdermal, buccal, sublingual, and intraocular) administration. The most suitable route may depend, for example, on the disease and condition of the individual to whom the pharmaceutical formulation will be administered. Pharmaceutical formulations may be presented in unit dosage form. Pharmaceutical formulations can be prepared by any suitable method. Methods of preparing pharmaceutical formulations can include making a compound provided herein (e.g., Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or its pharmaceutically acceptable The accepted salt, ester, amide, prodrug or solvate ("active ingredient") is contacted with one or more pharmaceutically acceptable carriers (eg, auxiliary ingredients). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

[0417] Pharmaceutical formulations of compounds provided herein (e.g., formulas I, IA, IA1, Compounds of any of IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) may be provided as discrete units. For example, formulations suitable for oral administration may be presented as capsules, cachets, and / or lozenges containing a predetermined amount of the compound (eg, active ingredient) in any suitable form; as a solvent (eg, aqueous or non-aqueous solvent). ) as a solution or suspension; as an emulsion (eg, an oil-in-water liquid emulsion or a water-in-oil liquid emulsion); or as a powder or granules. The active ingredient may additionally or alternatively be presented as a bolus, lick or paste.

[0418] Pharmaceutical formulations suitable for oral administration include lozenges, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. A tablet may 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, for example, by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent, or lubricating, surface active or dispersing agent. Molded tablets can be made, for example, by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with, for example, one or more fillers, such as lactose; one or more binders, such as one or more starches; and / or one or more lubricants, such as talc. or magnesium stearate; and one or more stabilizers optionally present. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers and other elements may also be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, optionally containing gums, gelling agents, polymers, solvents or combinations thereof. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0419] Comprising a compound provided herein (such as a compound of any one of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II) or a form thereof (such as salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) can be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion vote with. Formulations for injection may be presented in unit dosage form, eg, in ampoules, vials, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of sterile Liquid carriers such as saline or sterile pyrogen-free water. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. Comprising a compound provided herein (such as a compound of any one of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II) or a form thereof (such as salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) pharmaceutical compositions can be formulated into injection solutions, which can be aqueous or non-aqueous (oily) sterile solutions and can Contains one or more antioxidants, thickeners, suspending agents, buffers, solutes and / or bacteriostats. Addition of one or more such additives can render the formulation isotonic with the blood of the intended recipient (eg, an individual 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 polydextrose. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In addition to the formulations described elsewhere herein, compounds provided herein (e.g., formula A compound of any of I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) may also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials, eg, as emulsions in acceptable oils, or ion exchange resins, or as sparingly soluble derivatives, eg, as sparingly soluble salts. Suitable for buccal or sublingual administration comprising a compound provided herein (e.g., any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II compound) or its form (e.g. salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) the form. Such compositions may contain a flavored base such as sucrose and the active ingredient in acacia or tragacanth. Pharmaceutical compositions comprising a compound provided herein or a form thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) suitable for rectal administration may be formulated as a suppository or retention enema agents, and may contain vehicles such as cocoa butter, polyethylene glycols, or other glycerides. Certain compounds provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or forms thereof ( For example, salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) may be formulated for non-systemic administration, such as topical administration. This includes topical application of a compound or form thereof disclosed herein to the epidermis or buccal cavity, as well as instillation of such compound or form into the ears, eyes and nose such that the compound or form thereof does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0424] Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the irritated site, such as gels, liniments, lotions, creams, ointments or pastes, and formulations suitable for application to the eyes. , ear or nasal administration drops. The active ingredient for topical administration may, for example, comprise from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation. For administration by inhalation, a compound (e.g., a compound of any one of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II) or a form thereof ( For example, salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) are conveniently delivered from an insufflator, nebulizer pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may 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 may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds provided herein may be in the form of a dry powder composition, eg, a powder mix of the compound and a suitable powder base such as lactose or starch. Powder compositions may be presented in unit dosage form, eg, in capsules, cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler or insufflator.

[0426] 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., formula I, IA, IA1, IA2, IB, IB1, IB2, IC , ID, ID', IE, IF or II) or salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers thereof).

[0427] It is to be understood that, in addition to ingredients specifically described elsewhere herein, the formulations described herein may include other suitable agents having regard to the type of formulation in question, for example those suitable for oral administration which may include flavoring agents .

[0428] Compound (such as any compound of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II) or its form (such as salt, ester, mutual Isomers, prodrugs, zwitterionic forms, stereoisomers, etc.) can be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The dosage range for adults is generally 5 mg to 2 g per day. Lozenges or other presentations presented in discrete units may conveniently contain an amount of one or more compounds effective at such dose or as a plurality of such doses, e.g., containing 5 mg to 500 mg, Usually in units of about 10 mg to 200 mg.

[0429] The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. method

[0430] The present disclosure also provides a method of modulating KRAS (e.g., KRAS with a G12D mutation) comprising combining KRAS with a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB1, IB2 , IC, ID, ID', IE, IF or II) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof. For example, the present disclosure can provide a method of altering cellular phenotype, cellular proliferation, KRAS activity, biochemical output produced by active or inactive KRAS, expression of KRAS, and / or binding of KRAS to a natural binding partner . Any such characteristics can be monitored and can be altered upon contact of KRAS with a compound provided herein, or a form thereof. A method of modulating KRAS (eg, KRAS with a G12D mutation) can be a mode of disease, disorder or disorder (eg, cancer) treatment, biological assay, cellular assay, biochemical assay, and the like. The disclosure also provides for the use of compounds provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof for treating a disease, disorder or disorder in a subject in need thereof. For example, the present disclosure provides a method comprising providing (e.g., administering) an effective amount of a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB, A compound of any one of IB1, IB2, IC, ID, ID', IE, IF or II) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof. The disclosure also provides for the use of a compound comprising a compound provided herein (eg, a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or Pharmaceutical compositions of salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers are methods of treating a disease, disorder or condition in a subject in need thereof. For example, the disclosure provides a method comprising providing (e.g., administering) to an individual (e.g., a patient) in need thereof comprising an effective amount of a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB , IB1, IB2, IC, ID, ID', IE, IF or II) or a pharmaceutical combination of a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof thing. In some embodiments, the individual is known to have (eg, has been previously diagnosed with) a disease, disorder or condition, such as cancer. The disease, disorder or condition can be a KRAS-mediated disease, such as a cancer characterized by a G12D mutation in KRAS. In some embodiments, the compound administered to an individual in need thereof according to the methods described herein is a compound described in an Example, Example, Figure, or Table herein, or a stereoisomer thereof, or a pharmaceutically acceptable Salt. The disclosure also provides compounds as provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof, or a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient, which is Use as a medicament, such as a medicament for the treatment of a disease, disorder or condition, eg cancer. The disclosure also provides a compound as provided herein (eg, a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a salt thereof , ester, tautomer, prodrug, zwitterionic form or stereoisomer, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, for the manufacture of Agents for treating a disease, disorder or condition (eg cancer) in a subject in need thereof.

[0433] The disclosure also provides a compound provided herein (e.g., a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or Salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers thereof, or use of a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient, which For use in the treatment of a disease, disorder or condition (eg cancer) in a subject in need thereof.

[0434] The disclosure also provides a compound provided herein (e.g., a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or Salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers thereof, or use of a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient, which For use in the manufacture of a medicament for the treatment of a disease, disorder or condition, such as cancer, in a subject in need thereof.

[0435] The disclosure also provides a method of inhibiting KRAS (e.g., KRAS with a G12D mutation), e.g., in an individual in need thereof, comprising combining KRAS with a compound as provided herein (e.g., Formula I, IA , IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II any one of the compound) or a salt, ester, tautomer, prodrug, zwitterionic form or stereo isomers, or a pharmaceutical composition comprising any one of the aforementioned compounds and a pharmaceutically acceptable excipient. The disclosure also provides compounds as provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof, or a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient, which is For inhibiting KRAS (eg, KRAS with a G12D mutation) (eg, in an individual in need thereof). The disclosure also provides a compound as provided herein (eg, a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a salt thereof , ester, tautomer, prodrug, zwitterionic form or stereoisomer, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, for the manufacture of To inhibit KRAS (eg KRAS with G12D mutation) in individuals in need thereof. The disclosure also provides a compound provided herein (e.g., a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or Salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers thereof, or use of a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient, which It is used to inhibit KRAS (eg KRAS with G12D mutation) in an individual in need thereof.

[0438] The disclosure also provides a compound provided herein (e.g., a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or Salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers thereof, or use of a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient, which For use in the manufacture of a medicament for inhibiting KRAS (eg, KRAS with a G12D mutation) in an individual in need thereof.

[0439] The present disclosure also provides a method comprising administering to an individual (e.g., a patient) a therapeutically effective amount of a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II) or salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers thereof, thereby reducing, reducing, eliminating, stopping or One or more symptoms of the individual are ameliorated, such as one or more symptoms of a disease, disorder or condition (eg, cancer). In some embodiments, a therapeutically effective amount of a compound provided herein (e.g., of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II is administered. compound) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof slows or prevents tumor growth. In some embodiments, a therapeutically effective amount of a compound provided herein (e.g., of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II is administered. compound) or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof causes tumor shrinkage (eg, tumor regression).

[0440] In some embodiments of any of the methods, uses, and medicaments provided herein, the disease, disorder or condition is cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic duct adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), colorectal cancer (CRC), endometrial cancer, uterine carcinosarcoma, Ewing sarcoma , osteosarcoma, rhabdomyosarcoma, adrenocortical carcinoma, neuroblastoma, Wilm tumor, retinoblastoma, skin cancer, breast cancer, prostate cancer, head and neck cancer, or ovarian cancer. In some embodiments, the cancer is pancreatic cancer (eg, pancreatic duct adenocarcinoma), lung cancer (eg, non-small cell lung cancer adenocarcinoma), or colorectal cancer (CRC). In some embodiments, the cancer is pancreatic cancer (eg, pancreatic duct adenocarcinoma). In some embodiments, the cancer is lung cancer (eg, non-small cell lung cancer adenocarcinoma). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is or comprises a solid tumor.

[0441] In some embodiments, the disease, disorder or disorder is associated with KRAS, such as a disorder associated with KRAS mutation or KRAS dysregulation. In some embodiments, the disease, disorder or disorder is associated with the KRAS gene, such as a disease, disorder or disorder associated with a KRAS gene mutation or KRAS gene dysregulation. KRAS or a mutation or dysregulation of KRAS can 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 (eg, human K-Ras4a or K-Ras4b) signaling pathway activity, such as a disease, disorder or condition associated with aberrant KRAS signaling pathway activity. In some embodiments, the disease, disorder or condition is associated with a mutation or dysregulation of human K-Ras4b. In some embodiments, the disease, disorder or condition is associated with aberrant K-Ras4b signaling pathway activity. In some embodiments, the disease, disorder or condition is associated with a mutation or dysregulation of human K-Ras4a. In some embodiments, the disease, disorder or condition is associated with aberrant K-Ras4a signaling pathway activity. Drug administration and combination therapy

[0442] Compounds provided herein (e.g., compounds of any one of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) and forms thereof (e.g., salts , esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) or compositions comprising them (such as pharmaceutical compositions) can be administered in various modes (such as orally, topically or by injection) vote with. The amount of active ingredient (eg, a compound provided herein in any suitable form) administered to an individual (eg, a patient) will be the responsibility of the attending medical provider. The specific dosage level for a given individual (e.g., patient) will depend on a variety of factors, including, for example, the activity of the active ingredient being administered; the physical fitness of the individual (e.g., age, weight, height, body mass index, general health, Comorbidities, gender, etc.); other characteristics of the individual (such as diet, exercise level, ethnic origin, race, etc.); time of administration; route of administration; rate of excretion; drug combination; disease, disorder or condition being treated; Severity of disease, disorder or condition.

[0443] In some embodiments, a compound provided herein (eg, a compound of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) Forms thereof (eg, salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) are administered in combination with an additional agent, eg, an additional therapeutic agent. For example, if an individual experiences side effects such as high blood pressure after receiving a compound provided herein, or a form thereof, it may be appropriate to administer additional agents effective to manage the side effects, such as antihypertensive agents. In another example, a compound provided herein (e.g., a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a form thereof The therapeutic effectiveness of a drug can be enhanced by administering an adjuvant, which by itself may have only minimal therapeutic benefit, but in combination with another therapeutic agent may provide the individual with enhanced overall therapeutic benefit. In yet another example, a compound provided herein (e.g., a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a form thereof The therapeutic benefit of the compound can be enhanced by administering the compound, or an alternative form thereof, together with additional agents (which may comprise additional therapeutic regimens) that also provide therapeutic benefit. For example, a compound provided herein (e.g., a compound of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a form thereof can be combined with Additional agents effective to treat a disease, disorder or condition, such as cancer, are administered in combination. In general, a compound provided herein (e.g., a compound of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a form thereof is combined with a The combination of one or more additional agents (eg, therapeutic agents) can enhance the overall benefit experienced by an individual after receiving either component individually. In some embodiments, the effect can be additive. In some embodiments, the effect can be synergistic.

[0444] In some embodiments, a compound provided herein (eg, a compound of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) Forms thereof (eg, salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) are administered in combination with an anticancer agent (eg, a chemotherapeutic agent). Anticancer agents can be, for example, alkylating agents, antimitotic agents, checkpoint inhibitors, antimetabolites, plant alkaloids, terpenoids, cytotoxic agents, antibiotics, topoisomerase inhibitors, aromatase inhibitors, vascular Production inhibitors, antisteroids, antiandrogens, mTOR inhibitors, monoclonal antibodies, or tyrosine kinase inhibitors. The alkylating agent can be, for example, armustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin ( oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine ) (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, or cyclophosphamide (ENDOXAN) . Antimetabolites can be, for example, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C ), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEY), methotrexate ( RHEUMATREX) or raltitrexed. The antimitotic agent can be, for example, a taxane, such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL); or a vinca alkaloid, such as vincristine (ONCOVIN ), vinblastine, vindesine, or vinorelbine (NAVELBINE). Checkpoint inhibitors can be anti-PD-1 or anti-PD-L1 antibodies such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736 or MPDL3280A; anti-CTLA-4 antibodies Pilimumab (ipilimumab) (YERVOY); or targeting LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), Agents of TIM3 (containing T-cell immunoglobulin and mucin domain-3) or OX40 (tumor necrosis factor receptor superfamily member 4). The topoisomerase inhibitor can be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON) or etoposide (EPOSIN). Cytotoxic antibiotics can be, for example, actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), Doxorubicin daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE) or plicamycin. The aromatase inhibitor can be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR) or exemestane ( exemestane) (AROMASIN). An angiogenesis inhibitor may be, for example, genistein, sunitinib (SUTENT) or bevacizumab (AYASTIN). The antisteroid or antiandrogen may be, for example, amine glutetamide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN) or nilutamide (nilutamide) (NILANDRON). Tyrosine kinase inhibitors can be, for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib ( TYKERB ), sorafenib (NEXAVAR), or axitinib (INLYTA). The mTOR inhibitor can be, for example, everolimus, temsirolimus (TORISEL) or sirolimus. The monoclonal antibody can be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN). Additional examples of agents that may be suitable for use in combination with the compounds provided herein or alternative forms thereof include, but are not limited to, amsacrine; Bacillus Calmette-Guerin (B-C-G) vaccines; buserelin ( ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin ); dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interference interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; metformin mitotane (o,r'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; and radiation therapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluorohydroxymethyltestosterone ) (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES) and dienestrol; progestins such as medroxyprogesterone acetate (MPA ) and megestrol; and testosterone.

[0445] Two or more therapeutic agents, one of which is a compound provided herein (e.g., formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF or II any one of the compounds) or forms thereof, may be administered in any order or may be administered simultaneously. If administered simultaneously, the multiple therapeutic agents may be presented in a single unified form or in multiple forms (eg, as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not administered simultaneously, the time between doses can be any duration ranging from a few minutes to four weeks.

[0446] Accordingly, in another aspect, the present disclosure provides a method for treating a disease, disorder or condition (eg, cancer) in a subject (eg, a human or animal subject) in need thereof, the method comprising administering The subject is administered an amount of a compound provided herein (e.g., a compound of any of Formula I, IA, IIA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a form thereof (eg, salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.), in combination with at least one additional agent for the treatment of a disease, disorder or disorder. In a related aspect, the disclosure provides a composition (e.g., a pharmaceutical composition) comprising a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID , ID', IE, IF or II) or forms thereof (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.), and at least one An additional agent in the treatment of a disease, disorder or condition such as cancer.

[0447] In some embodiments, the methods provided herein are used to treat a disease, disorder, or disorder (e.g., cancer) comprising administering to a subject in need thereof a therapeutically effective amount of Formula I, IA, IA1, IA2, IB , IB1, IB2, IC, ID, ID', IE, IF or II of any one of the compound or a pharmaceutically acceptable salt thereof, wherein the disease, disease or condition is responsive to one or more chemotherapeutic drugs and and / or cancers resistant to ionizing radiation. In some embodiments, the methods provided herein are used to treat a disease, disorder, or condition (e.g., cancer) comprising administering to a subject in need thereof a therapeutically effective amount of Formula I, IA, IIA1, IA2, IB, IB1, A compound of any one of IB2, IC, ID, ID', IE, IF or II, or a pharmaceutically acceptable salt thereof, in combination with an additional agent, wherein the disease, disorder or condition is responsive to one or more chemotherapy treatments Cancers resistant to drugs and / or ionizing radiation.

[0448] The compounds, compositions and methods disclosed herein are useful in the treatment of a disease, disorder or condition, such as cancer. In certain embodiments, the disease is one of a disorder of cell proliferation, including cancer. Cancers can be hormone-dependent or hormone-resistant, such as in the case of breast cancer. In certain embodiments, the cancer is or comprises a solid tumor. In other embodiments, the cancer is lymphoma or leukemia. In certain embodiments, the cancer is a drug-resistant phenotype of a cancer disclosed herein or otherwise known. Tumor invasion, tumor growth, tumor metastasis, and angiogenesis can also be treated using the compositions and methods disclosed herein. In some embodiments, the compounds, compositions and methods provided herein are also useful for treating precancerous neoplasia. Cancers that may be treated by the methods disclosed herein include, but are not limited to, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, and prostate cancer; oral and pharyngeal cancer Cancer of the body (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, liver and biliary tract; pancreas, bone, connective tissue, skin, cervix, uterus, endometrium , testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); eye, brain, spinal cord and other components of the central and peripheral nervous system and associated structures such as meninges; and thyroid and other Cancer of the endocrine glands. The term "cancer" also covers cancers that do not necessarily form solid tumors, including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and hematopoietic malignancies, including leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML)), and lymphoma, including lymphocytic, granular and Nuclear lymphoma. Additional types of cancer that can be treated using the compounds and methods provided herein include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, glioblastoma , chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endothelial sarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric carcinoma , urogenital cancer, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, liver cancer, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, fat Sarcoma, lymphatic system carcinoma, lymphoma, lymphangiosarcoma, lymphatic endothelial sarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myeloma, myxosarcoma neuroblastoma, neurofibrosarcoma, oligotree Glioblastoma, osteogenic sarcoma, epithelial ovarian carcinoma, papillary carcinoma, papillary adenocarcinoma, paraganglioma, parathyroidoma, pheochromocytoma, pineal tumor, plasmacytoma , retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancer, melanoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, sweat gland carcinoma, synovoma, thyroid carcinoma, uveal melanoma tumor and Wilm's tumor. Additional diseases and conditions that may be treated by the methods disclosed herein include, but are not limited to, diseases or conditions associated with KRAS, such as those associated with KRAS mutations or KRAS dysregulation, and diseases or conditions associated with the KRAS gene, such as Diseases or conditions associated with KRAS gene mutation or KRAS gene dysregulation.

[0450] In some embodiments, the compounds, compositions and methods provided herein are useful for preventing and / or reducing tumor invasion, growth and / or metastasis.

[0451] The compounds, compositions, and methods provided herein are applicable to the treatment of humans as well as veterinary treatment of non-human animals, including companion animals, exotic animals, and farm animals (such as described herein), including mammals, rodents, and the like . For example, the compounds, compositions and methods provided herein can be adapted for use in the treatment of horses, dogs or cats. Listed Examples

[0452] Embodiment 1-1. A compound represented by formula I: (I) or its salt (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or Stereoisomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring containing a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; R2 is selected from H and C1- 6 alkyl; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocycle or heterocycle is unsubstituted or substituted by one or A plurality of R10 substitutions; or R2 and R3 form a heterocyclic ring unsubstituted or substituted by one or more R11 with the atoms they are connected to; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbon The ring and heterocycle are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 members Carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or more R14; R6 It is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, either of which is unsubstituted or via a or multiple R16 substitutions; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or One or more R18 substitutions; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl )N(R19)2, -(C1-6alkyl)C(O)N(R19)2,-C(NR19)NR19CN and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or One or more R20 substitutions; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl )N(R19)2, -(C1-6alkyl)C(O)N(R19)2,-C(NR19)NR19CN and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or One or more R20 substitutions; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or through one or more R13 is substituted; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1- 6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or Multiple R13 substitutions; each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently is selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently Selected from C1-6 alkyl, C2-6 alkenyl and H.

[0453] Embodiment 1-2. The compound of embodiment 1-1, wherein R1 is -OR8.

[0454] The compound of embodiment 1-3. embodiment 1-2, wherein R8 is a heterocycle.

[0455] The compound of embodiment 1-4. embodiment 1-3, wherein R8 is an alkyl heterocycle.

[0456] Embodiment 1-5. The compound of embodiment 1-3 or 1-4, wherein R8 comprises a heterocycle comprising at least one nitrogen atom.

[0457] Embodiment 1-6. The compound of any one of embodiments 1-3 to 1-5, wherein the heterocycle comprises one or more R16 substituents.

[0458] Embodiment 1-7. The compound of embodiment 1-6, wherein at least one R16 is -OR12, wherein R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0459] Embodiment 1-8. The compound of embodiment 1-7, wherein at least one R16 is -OCH3.

[0460] The compound of embodiment I-9. embodiment I-1, wherein R1 is selected from: ,,,,,,,,,,,,, and.

[0461] The compound of embodiment I-10. embodiment I-1, wherein R1 is selected from: ,,,,,,,, and.

[0462] Embodiment I-11. The compound of embodiment I-1, wherein R1 is a 4-6 membered heterocyclic ring comprising a nitrogen atom, and the heterocyclic ring is unsubstituted or substituted by one or more R16.

[0463] The compound of embodiment 1-12. embodiment 1-11, wherein R1 is selected from: , and.

[0464] The compound of embodiment 1-13. embodiment 1-1, wherein R1 is H.

[0465] Embodiment 1-14. The compound of any one of Embodiments 1-1 to 1-13, wherein R2 is H.

[0466] Embodiment 1-15. The compound of any one of Embodiments 1-1 to 1-13, wherein R2 is C1-6 alkyl.

[0467] Embodiment 1-16. The compound of any one of embodiments 1-1 to 1-15, wherein R3 is C1-6 alkyl, and the C1-6 alkyl is substituted by one or more R9.

[0468] Embodiment 1-17. The compound of embodiment 1-16, wherein R3 is C1-6 alkyl substituted by -N(R17)2, wherein each R17 is independently selected from C1-6 alkyl and H .

[0469] The compound of embodiment 1-18. embodiment 1-17, wherein R3 is C1-6 alkyl substituted by -NH2.

[0470] Embodiment 1-19. The compound of any one of Embodiments 1-1 to 1-15, wherein R3 is selected from the group consisting of: , , , and.

[0471] Embodiment 1-20. The compound of any one of Embodiments 1-1 to 1-15, wherein R3 is a carbocycle that is unsubstituted or substituted by one or more R10.

[0472] Embodiment 1-21. The compound of embodiment 1-20, wherein R3 is a carbocycle substituted by -N(R19), wherein each R19 is independently selected from unsubstituted or substituted C1-6 Alkyl and H.

[0473] The compound of embodiment 1-22. embodiment 1-21, wherein R3 is a carbocycle substituted by -NH2.

[0474] Embodiment I-23. The compound of any one of Embodiments I-1 to I-15, wherein R3 is selected from C1-6 alkyl-N(R17)C(O)C1-6 alkylN (R17)2.

[0475] Embodiment 1-24. The compound of any one of Embodiments 1-1 to 1-15, wherein R3 is a heterocycle that is unsubstituted or substituted with one or more R10.

[0476] The compound of embodiment 1-25. embodiment 1-24, wherein the heterocycle contains one or more nitrogen atoms.

[0477] Embodiment 1-26. The compound of embodiment 1-24 or 1-25, wherein R3 is a heterocyclic ring substituted by -N(R19), wherein each R19 is independently selected from unsubstituted or substituted C1-6 alkyl and H.

[0478] The compound of embodiment 1-27. embodiment 1-26, wherein R3 is a heterocyclic ring substituted by -NH2.

[0479] Embodiment 1-28. The compound of any one of Embodiments 1-1 to 1-15, wherein R3 is selected from: , , , , , , , , and, any of which is unsubstituted or One or more R10 substitutions.

[0480] Embodiment 1-29. The compound of any one of Embodiments 1-15 to 1-28, wherein R2 or R3 comprises an amine moiety.

[0481] Embodiment 1-30. The compound of any one of Embodiments 1-1 to 1-13, wherein R2 and R3 together form an unsubstituted atom (such as a nitrogen atom) with which it is attached or through one or more A heterocyclic ring substituted by R11.

[0482] Embodiment 1-31. The compound of embodiment 1-30, wherein R and R form a heterocyclic ring with the following structure together with the atoms connected to it: ,,,,,,,,,,,,, and, wherein Either is unsubstituted or substituted with one or more R11.

[0483] Embodiment 1-32. The compound of embodiment 1-30, wherein R2 and R3 form a heterocyclic ring with the following structure together with the atoms to which they are attached: ,,,,,,,,, and.

[0484] Embodiment 1-33. The compound of any one of Embodiments 1-30 to 1-32, wherein R and R form a heterocyclic ring together with the nitrogen atom to which they are attached, and the heterocyclic ring (i) includes an additional nitrogen atom Or (ii) substituted with a group comprising an amine moiety.

[0485] Embodiment 1-34. The compound of any one of Embodiments 1-1 to 1-33, wherein R4 is hydrogen.

[0486] Embodiment 1-35. The compound of any one of Embodiments 1-1 to 1-33, wherein R4 is halogen.

[0487] Embodiment 1-36. The compound of any one of Embodiments 1-1 to 1-35, wherein R5 is halogen.

[0488] Embodiment 1-37. The compound of any one of Embodiments 1-1 to 1-36, wherein R7 is halogen.

[0489] Embodiment 1-38. The compound of any one of Embodiments 1-1 to 1-37, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0490] Embodiment 1-39. The compound of embodiment 1-38, wherein R6 is selected from: , , , and.

[0491] The compound of embodiment 1-40. embodiment 1-39, wherein R6 is: , and.

[0492] Embodiment 1-41. A compound represented by formula IA: (IA) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or Stereoisomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring containing a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; R2 is H; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10; R4 is selected From H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered heterocyclic ring, any C1-6 alkyl Unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic rings are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle And the heterocycle is unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle And alkyl heterocycles, any of which is unsubstituted or substituted by one or more R16; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and - OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N (R19 )2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1- 6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl Base or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkane wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1- 6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently are selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2 , -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0493] Embodiment 1-42. The compound of embodiment 1-41, wherein R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10.

[0494] Embodiment 1-43. The compound of embodiment 1-42, wherein R3 is a 3-6 membered carbocyclic or heterocyclic ring that is unsubstituted or substituted by one or more R10.

[0495] Embodiment 1-44. The compound of embodiment 1-43, wherein R3 is selected from: ,,,,,,, and, any of which is unsubstituted or substituted by one or more R10.

[0496] Embodiment 1-45. The compound of embodiment 1-41, wherein R3 is selected from C1-6 alkyl substituted by one or more R9.

[0497] Embodiment 1-46. The compound of embodiment 1-45, wherein R3 is selected from C1-6 alkyl-N(R17)2.

[0498] Embodiment 1-47. The compound of embodiment 1-45 or 1-46, wherein R3 is selected from: , , , and.

[0499] Embodiment I-48. The compound of embodiment I-45, wherein R3 is selected from C1-6 alkyl-N(R17)C(O)C1-6 alkyl N(R17)2.

[0500] Embodiment 1-49. The compound of any one of Embodiments 1-41 to 1-48, wherein R3 comprises an amine moiety.

[0501] Embodiment 1-50. The compound of any one of Embodiments 1-41 to 1-49, wherein R1 is H.

[0502] Embodiment 1-51. The compound of any one of Embodiments 1-41 to 1-50, wherein R1 is -OR8.

[0503] Embodiment 1-52. The compound of embodiment 1-51, wherein R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted by one or more R14.

[0504] Embodiment 1-53. The compound of embodiment 1-51 or 1-52, wherein R1 is selected from: ,,,,,,,,,,,,, and.

[0505] Embodiment 1-54. The compound of embodiment 1-51 or 1-52, wherein R1 is selected from: ,,,,,,,, and.

[0506] Embodiment 1-55. The compound of any one of Embodiments 1-41 to 1-54, wherein R1 is a 4-6 membered heterocyclic ring comprising a nitrogen atom, which is unsubstituted or modified by one or more R16 replacement.

[0507] The compound of embodiment 1-56. embodiment 1-55, wherein R1 is selected from: , and.

[0508] Embodiment 1-57. The compound of any one of Embodiments 1-41 to 1-56, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0509] Embodiment 1-58. The compound of embodiment 1-57, wherein R6 is selected from: , , , and.

[0510] Embodiment 1-59. The compound of Embodiment 1-58, wherein R6 is: , and.

[0511] Embodiment 1-60. The compound of any one of Embodiments 1-41 to 1-59, wherein R4 is H.

[0512] Embodiment 1-61. The compound of any one of Embodiments 1-41 to 1-59, wherein R4 is halogen.

[0513] Embodiment 1-62. The compound of any one of Embodiments 1-41 to 1-61, wherein R5 is halogen.

[0514] Embodiment 1-63. The compound of any one of Embodiments 1-41 to 1-62, wherein R7 is halogen.

[0515] Embodiment 1-64. A compound according to formula IA1: (IA1) or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, a zwitterionic form or a stereo Isomers, wherein: R1 is H; R2 is H; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocycle Or the heterocycle is unsubstituted or substituted by one or more R10; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 1-membered carbocyclic ring and 3-6 membered heterocyclic ring, wherein any C1-6 alkyl group is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered heterocyclic ring, wherein any C1-6 alkane The group is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkane The group is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O) (C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O)N(R19)2,-C(NR19)NR19CN and C1-6 alkyl, any C1-6 alkyl The group is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O) (C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O)N(R19)2,-C(NR19)NR19CN and C1-6 alkyl, any C1-6 alkyl The base is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted Or substituted by one or more R13; Each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; Each R14 is independently selected from halogen, N(R12)2 and C1-6 alkane wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is not Substituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, - NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from- OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1- 6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0516] Embodiment 1-65. The compound of embodiment 1-64, wherein R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10.

[0517] Embodiment 1-66. The compound of embodiment 1-65, wherein R3 is selected from: , , , , , , , and, any of which is unsubstituted or substituted by one or more R10.

[0518] Embodiment 1-67. The compound of embodiment 1-64, wherein R3 is selected from C1-6 alkyl substituted by one or more R9.

[0519] The compound of embodiment 1-68. embodiment 1-67, wherein R3 is selected from: ,,,, and.

[0520] Embodiment I-69. The compound of Embodiment I-64, wherein R3 is selected from C1-6 alkyl-N(R17)C(O)C1-6 alkylN(R17)2.

[0521] Embodiment 1-70. The compound of any one of Embodiments 1-64 to 1-68, wherein R3 comprises an amine moiety.

[0522] Embodiment 1-71. The compound of any one of Embodiments 1-62 to 1-70, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0523] The compound of embodiment 1-72. embodiment 1-71, wherein R6 is selected from: ,,, and.

[0524] The compound of embodiment 1-73. embodiment 1-72, wherein R6 is: , and.

[0525] Embodiment 1-74. The compound of any one of Embodiments 1-64 to 1-73, wherein R4 is H.

[0526] Embodiment 1-75. The compound of any one of Embodiments 1-64 to 1-73, wherein R4 is halogen.

[0527] Embodiment 1-76. The compound of any one of Embodiments 1-64 to 1-75, wherein R5 is halogen.

[0528] Embodiment 1-77. The compound of any one of Embodiments 1-64 to 1-76, wherein R7 is halogen.

[0529] Embodiment 1-78. A compound according to formula IA2: (IA2) or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, a zwitterionic form or a stereo Isomers, wherein: R1 is -OR8; R2 is H; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbon The ring or heterocycle is unsubstituted or substituted by one or more R10; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- 6-membered carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or more R14 ; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered heterocyclic ring, wherein any C1-6 Alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or substituted by one or more R16; each R9 is independently selected from -N (R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from- N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl) C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1 -6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN , -N(R22)2 and halogen; Each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; Each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, - N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1- 6 alkyl groups are unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H .

[0530] Embodiment 1-79. The compound of embodiment 1-78, wherein R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted by one or more R14.

[0531] The compound of embodiment 1-80. embodiment 1-78, wherein R1 is selected from: ,,,,,,,,,,,,, and.

[0532] The compound of embodiment 1-81. embodiment 1-78, wherein R1 is selected from: ,,,,,,,, and.

[0533] Embodiment 1-82. The compound of any one of Embodiments 1-78 to 1-81, wherein R is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or modified by one or Multiple R10 substitutions.

[0534] Embodiment 1-83. The compound of embodiment 1-82, wherein R3 is selected from: , , , , , , , and, any of which is unsubstituted or substituted by one or more R10.

[0535] Embodiment 1-84. The compound of any one of Embodiments 1-78 to 1-83, wherein R3 is selected from C1-6 alkyl substituted with one or more R9.

[0536] The compound of embodiment 1-85. embodiment 1-84, wherein R3 is selected from: ,,,, and.

[0537] Embodiment 1-86. The compound of any one of Embodiments 1-78 to 1-85, wherein R3 is selected from C1-6 alkyl-N(R17)C(O)C1-6 alkylN (R17)2.

[0538] Embodiment 1-87. The compound of any one of Embodiments 1-78 to 1-86, wherein R3 comprises an amine moiety.

[0539] Embodiment 1-88. The compound of any one of Embodiments 1-78 to 1-87, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0540] Embodiment 1-89. The compound of embodiment 1-88, wherein R6 is selected from: , , , and.

[0541] The compound of embodiment 1-90. embodiment 1-89, wherein R6 is: , and.

[0542] Embodiment 1-91. The compound of any one of Embodiments 1-78 to 1-90, wherein R4 is H.

[0543] Embodiment 1-92. The compound of any one of Embodiments 1-78 to 1-90, wherein R4 is halogen.

[0544] Embodiment 1-93. The compound of any one of Embodiments 1-78 to 1-92, wherein R5 is halogen.

[0545] Embodiment 1-94. The compound of any one of Embodiments 1-78 to 1-93, wherein R7 is halogen.

[0546] Embodiment 1-95. A compound according to formula IB: (IB) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or stereo Isomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring containing a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; ring A is unsubstituted or substituted by one Or multiple R11 substituted heterocycles; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3- 6-membered heterocyclic ring, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered heterocyclic ring, wherein any C1-6 alkyl is unsubstituted or One or more R13 are substituted, and any carbocycle and heterocycle are unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12 , - CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or substituted by one or more R16; each R11 is independently selected from -N(R19)2, -C (O )R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C(O)N(R19) 2. -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 Alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and Halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen , N (R12) 2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N (R12) 2, C1- 6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is not Substituted or substituted by one or more R21; Each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; Each R21 is independently selected from - OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0547] Embodiment 1-96. The compound of embodiment 1-95, wherein ring A is a 4-6 membered heterocyclic ring that is unsubstituted or substituted by one or more R11.

[0548] The compound of embodiment 1-97. embodiment 1-95, wherein ring A has the following structure: ,,,,,,,,,,,,, and, the ring is unsubstituted or through one or more R11 replace.

[0549] Embodiment 1-98. The compound of embodiment 1-95, wherein ring A has the following structure: ,,,,,,,,, and.

[0550] Embodiment 1-99. The compound of any one of Embodiments 1-95 to 1-98, wherein Ring A comprises at least two nitrogen atoms and / or is substituted with a group comprising an amino moiety.

[0551] Embodiment 1-100. The compound of any one of Embodiments 1-95 to 1-99, wherein R1 is H.

[0552] Embodiment 1-101. The compound of any one of Embodiments 1-95 to 1-99, wherein R1 is -OR8.

[0553] Embodiment 1-102. The compound of embodiment 1-101, wherein R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted by one or more R14.

[0554] The compound of embodiment 1-103. embodiment 1-101, wherein R1 is selected from: ,,,,,,,,,,,,, and.

[0555] The compound of embodiment 1-104. embodiment 1-101, wherein R1 is selected from: ,,,,,,,, and.

[0556] Embodiment 1-105. The compound of any one of Embodiments 1-95 to 1-99, wherein R1 is a 4-6 membered heterocyclic ring comprising a nitrogen atom, which is unsubstituted or modified by one or more R16 replacement.

[0557] The compound of embodiment 1-106. embodiment 1-105, wherein R1 is selected from: , and.

[0558] Embodiment 1-107. The compound of any one of Embodiments 1-95 to 1-106, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0559] The compound of embodiment 1-108. embodiment 1-107, wherein R6 is selected from: , , , and.

[0560] The compound of embodiment 1-109. embodiment 1-108, wherein R6 is: , and.

[0561] Embodiment 1-110. The compound of any one of Embodiments 1-95 to 1-109, wherein R4 is H.

[0562] Embodiment 1-111. The compound of any one of Embodiments 1-95 to 1-109, wherein R4 is halogen.

[0563] Embodiment 1-112. The compound of any one of Embodiments 1-95 to 1-111, wherein R5 is halogen.

[0564] Embodiment 1-113. The compound of any one of Embodiments 1-95 to 1-112, wherein R7 is halogen.

[0565] Embodiment 1-114. A compound according to formula IB1: (IB1) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or stereo Isomers, wherein: Ring A is a heterocycle unsubstituted or substituted by one or more R11; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle are unsubstituted Or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 member carbocycle and 3-6 member Heterocyclic, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R6 is substituted by one or more R15 Substituted bicyclic heteroaryl; R7 is selected from halogen, -OR12, -CN and H; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19 )2, -C (O) (C1-6 alkyl) N (R19) 2, - (C1-6 alkyl) C (O) N (R19) 2, -C (NR19) NR19CN and C1-6 alkane wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N( R12) 2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21 is substituted; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkane and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0566] Embodiment 1-115. The compound of embodiment 1-114, wherein ring A is a 4-6 membered heterocyclic ring that is unsubstituted or substituted by one or more R11.

[0567] The compound of embodiment 1-116. embodiment 1-114, wherein ring A has the following structure: ,,,,,,,,,,,,, and, the ring is unsubstituted or through one or more R11 replace.

[0568] Embodiment 1-117. The compound of embodiment 1-114, wherein ring A has the following structure: ,,,,,,,,, and.

[0569] Embodiment 1-118. The compound of any one of Embodiments 1-114 to 1-117, wherein Ring A comprises at least two nitrogen atoms and / or is substituted with a group comprising an amino moiety.

[0570] Embodiment 1-119. The compound of any one of embodiments 1-114 to 1-118, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0571] The compound of embodiment 1-120. embodiment 1-119, wherein R6 is selected from: , , , and.

[0572] The compound of embodiment 1-121. embodiment 1-120, wherein R6 is: , and.

[0573] Embodiment 1-122. The compound of any one of Embodiments 1-114 to 1-121, wherein R4 is H.

[0574] Embodiment 1-123. The compound of any one of Embodiments 1-114 to 1-121, wherein R4 is halogen.

[0575] Embodiment 1-124. The compound of any one of Embodiments 1-114 to 1-123, wherein R5 is halogen.

[0576] Embodiment 1-125. The compound of any one of Embodiments 1-114 to 1-124, wherein R7 is halogen.

[0577] Embodiment 1-126. A compound according to formula IB2: (IB2) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or stereo Isomers, wherein: R1 is -OR8; Ring A is a heterocycle unsubstituted or substituted by one or more R11; R4 is H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 Alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle Unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3 -6-membered heterocyclic ring, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R6 is substituted by one or more R14; Multiple R15 substituted bicyclic heteroaryls; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or through one or more R16 Substitution; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19) 2. -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or through one or more R20 Substitution; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is not Substituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; Each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R19 is independently selected from From C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2 , -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0578] Embodiment 1-127. The compound of embodiment 1-126, wherein ring A is a 4-6 membered heterocyclic ring that is unsubstituted or substituted by one or more R11.

[0579] The compound of embodiment 1-128. embodiment 1-126, wherein ring A has the following structure: ,,,,,,,,,,,,, and, the ring is unsubstituted or through one or more R11 replace.

[0580] Embodiment 1-129. The compound of embodiment 1-126, wherein ring A has the following structure: ,,,,,,,,, and.

[0581] Embodiment 1-130. The compound of any one of Embodiments 1-126 to 1-129, wherein Ring A comprises at least two nitrogen atoms and / or is substituted with a group comprising an amino moiety.

[0582] Embodiment 1-131. The compound of any one of embodiments 1-126 to 1-130, wherein R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted with one or more R14.

[0583] Embodiment 1-132. The compound of any one of embodiments 1-126 to 1-131, wherein R is selected from the group consisting of: ,,,,,,,,,,,, and.

[0584] Embodiment 1-133. The compound of any one of Embodiments 1-126 to 1-131, wherein R1 is selected from the group consisting of: ,,,,,,, and.

[0585] Embodiment 1-134. The compound of any one of embodiments 1-126 to 1-133, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0586] The compound of embodiment 1-135. embodiment 1-134, wherein R6 is selected from: , , , and.

[0587] The compound of embodiment 1-136. embodiment 1-135, wherein R6 is: , and.

[0588] Embodiment 1-137. The compound of any one of Embodiments 1-126 to 1-136, wherein R4 is H.

[0589] Embodiment 1-138. The compound of any one of Embodiments 1-126 to 1-136, wherein R4 is halogen.

[0590] Embodiment 1-139. The compound of any one of Embodiments 1-126 to 1-138, wherein R5 is halogen.

[0591] Embodiment 1-140. The compound of any one of Embodiments 1-126 to 1-139, wherein R7 is halogen.

[0592] Embodiment 1-141. A compound according to formula IC: (IC) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or stereo Isomers, wherein: R2 is selected from H and C1-6 alkyl; R3 is selected from C1-6 alkyl, carbocyclic and heterocyclic, wherein any C1-6 alkyl is substituted by one or more R9, and Wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted by one or more R10; or R2 and R3 form a heterocyclic ring which is unsubstituted or substituted by one or more R11 together with the atoms they are connected to; R4 is H, halogen , -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon ring and 3-6 membered heterocyclic ring, wherein any C1-6 alkyl is unsubstituted or Substituted by one or more R13, and any carbocycle and heterocycle are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkene , C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl group is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle are not Substituted or substituted by one or more R14; R6 is a bicyclic heteroaryl substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; each R9 is independently selected from -N( R17) 2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N (R19 )2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C (O) N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N (R19 )2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C (O) N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1- 6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; Each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H , wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and Halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2- 6 alkenyl and H.

[0593] Embodiment 1-142. The compound of embodiment 1-141, wherein R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10.

[0594] Embodiment 1-143. The compound of embodiment 1-141, wherein R3 is selected from: ,,,,,,, and, any of which is unsubstituted or substituted by one or more R10.

[0595] Embodiment 1-144. The compound of any one of Embodiments 1-141 to 1-143, wherein R3 is selected from C1-6 alkyl substituted with one or more R9.

[0596] The compound of embodiment 1-145. embodiment 1-144, wherein R3 is selected from: ,,,, and.

[0597] Embodiment I-146. The compound of any one of Embodiments I-141 to I-145, wherein R3 is selected from C1-6 alkyl-N(R17)C(O)C1-6 alkylN (R17)2.

[0598] Embodiment 1-147. The compound of any one of Embodiments 1-141 to 1-146, wherein R3 comprises an amine moiety.

[0599] Embodiment 1-148. The compound of embodiment 1-141, wherein R2 and R3 form a 4-6 membered heterocycle unsubstituted or substituted by one or more R11 together with the atoms to which they are attached.

[0600] Embodiment 1-149. The compound of embodiment 1-141, wherein R2 and R3 form a heterocyclic ring with the following structure together with the atoms they are connected to: ,,,,,,,,,,,, and, the Rings are unsubstituted or substituted with one or more R11.

[0601] Embodiment 1-150. The compound of embodiment 1-141, wherein R2 and R3 form a heterocyclic ring with the following structure together with the atoms to which they are attached: ,,,,,,,,, and.

[0602] Embodiment 1-151. The compound of any one of Embodiments 1-148 to 1-150, wherein R and R form a heterocycle with the atoms to which they are attached, the heterocycle (i) comprising an additional nitrogen atom or (ii) Substituted with a group including an amine moiety.

[0603] Embodiment I-152. The compound of any one of Embodiments I-141 to I-151, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0604] The compound of embodiment 1-153. embodiment 1-152, wherein R6 is selected from: ,,, and.

[0605] The compound of embodiment 1-154. embodiment 1-153, wherein R6 is: , and.

[0606] Embodiment 1-155. The compound of any one of Embodiments 1-141 to 1-154, wherein R4 is H.

[0607] Embodiment 1-156. The compound of any one of Embodiments 1-141 to 1-154, wherein R4 is halogen.

[0608] Embodiment 1-157. The compound of any one of Embodiments 1-141 to 1-156, wherein R5 is halogen.

[0609] Embodiment 1-158. The compound of any one of Embodiments 1-141 to 1-157, wherein R7 is halogen.

[0610] Embodiment 1-159. A compound according to formula ID: (ID) or a salt thereof (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or stereo Isomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring containing nitrogen atoms, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; R2 is selected from H and C1-6 Alkyl; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more Each R10 is substituted; or R2 and R3 form an unsubstituted or substituted heterocyclic ring with one or more R11 with the atoms they are connected to; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle And the heterocycle is unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbon Ring and 3-6 membered heterocyclic ring, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocyclic and heterocyclic ring is unsubstituted or substituted by one or more R14; R7 is Selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, any of which is unsubstituted or substituted by one or more R16; each R9 is independently selected from -N( R17) 2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N (R19 )2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C (O) N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N (R19 )2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl)N(R19)2, -(C1-6 alkyl)C (O) N(R19)2, -C(NR19)NR19CN and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1- 6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N (R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 are independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 The alkyl group is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently is selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H. R23 is selected from -N (R12) 2 and C1-6 alkyl-N (R12) 2; R24, R25 and R26 are independently selected from H, halogen, -OR12 and C1-6 alkyl, wherein any C1- 6 alkyl is unsubstituted or substituted by one or more R11; and each R27 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen.

[0611] Embodiment I-160. The compound of embodiment I-159, wherein R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10.

[0612] Embodiment 1-161. The compound of embodiment 1-159, wherein R3 is selected from: ,,,,,,, and, any of which is unsubstituted or substituted by one or more R10.

[0613] The compound of embodiment I-162. embodiment I-159, wherein R3 is selected from C1-6 alkyl substituted by one or more R9.

[0614] The compound of embodiment 1-163. embodiment 1-162, wherein R3 is selected from: ,,,, and.

[0615] Embodiment I-164. The compound of embodiment I-159, wherein R3 is selected from C1-6 alkyl-N(R17)C(O)C1-6 alkyl N(R17)2.

[0616] Embodiment 1-165. The compound of any one of Embodiments 1-159 to 1-164, wherein R3 comprises an amine moiety.

[0617] Embodiment 1-166. The compound of embodiment 1-159, wherein R2 and R3 together form a 4-6 membered heterocyclic ring which is unsubstituted or substituted by one or more R11 with the atoms to which they are attached.

[0618] Embodiment 1-167. The compound of embodiment 1-159, wherein R2 and R3 form a heterocyclic ring with the following structure together with the atoms they are connected to: ,,,,,,,,,,,, and, the Rings are unsubstituted or substituted with one or more R11.

[0619] Embodiment 1-168. The compound of embodiment 1-159, wherein R2 and R3 form a heterocyclic ring with the following structure together with the atoms to which they are attached: ,,,,,,,,, and.

[0620] Embodiment 1-169. The compound of any one of Embodiments 1-166 to 1-168, wherein R and R form a heterocycle with the atoms to which they are attached, the heterocycle (i) comprising an additional nitrogen atom or (ii) Substituted with a group including an amine moiety.

[0621] Embodiment 1-170. The compound of any one of Embodiments 1-159 to 1-169, wherein R1 is H.

[0622] Embodiment 1-171. The compound of any one of Embodiments 1-159 to 1-169, wherein R1 is -OR8.

[0623] Embodiment 1-172. The compound of embodiment 1-171, wherein R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted by one or more R14.

[0624] Embodiment 1-173. The compound of any one of Embodiments 1-159 to 1-169, wherein R is selected from the group consisting of: ,,,,,,,,,,,, and.

[0625] Embodiment 1-174. The compound of any one of Embodiments 1-159 to 1-169, wherein R1 is selected from the group consisting of: ,,,,,,, and.

[0626] Embodiment 1-175. The compound of any one of Embodiments 1-159 to 1-169, wherein R1 is a 4-6 membered heterocyclic ring comprising a nitrogen atom, which is unsubstituted or modified by one or more R16 replacement.

[0627] The compound of embodiment 1-176. embodiment 1-175, wherein R1 is selected from: , and.

[0628] Embodiment 1-177. The compound of any one of Embodiments 1-159 to 1-176, wherein R4 is H.

[0629] Embodiment 1-178. The compound of any one of Embodiments 1-159 to 1-176, wherein R4 is halogen.

[0630] Embodiment 1-179. The compound of any one of Embodiments 1-159 to 1-178, wherein R5 is halogen.

[0631] Embodiment 1-180. The compound of any one of Embodiments 1-159 to 1-179, wherein R7 is halogen.

[0632] Embodiment 1-181. The compound of any one of Embodiments 1-159 to 1-180, wherein R23 is -N(R12)2.

[0633] The compound of embodiment 1-182. embodiment 1-181, wherein R23 is -NH2.

[0634] Embodiment 1-183. The compound of any one of Embodiments 1-159 to 1-182, wherein R24 is halogen.

[0635] Embodiment 1-184. The compound of any one of Embodiments 1-159 to 1-183, wherein R25 and R26 are H.

[0636] Embodiment 1-185. A compound according to formula II: (II) or a salt (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or stereo Isomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring containing nitrogen atoms, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; R2 is selected from H and C1-6 Alkyl; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more Each R10 is substituted; or R2 and R3 form an unsubstituted or substituted heterocyclic ring with one or more R11 with the atoms they are connected to; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle And the heterocycle is unsubstituted or substituted by one or more R14; R6 is a bicyclic heteroaryl substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle And alkyl heterocycles, any of which is unsubstituted or substituted by one or more R16; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and - OR17, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R18; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N (R19 )2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1- 6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N (R19 )2, -C(O)(C1-6 alkyl) N(R19)2, -(C1-6 alkyl)C(O)N(R19)2, -C(NR19)NR19CN and C1- 6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R20; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl Base or C2-6 alkenyl is unsubstituted or substituted by one or more R13; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R16 is independently selected from halogen, -N(R12)2, C1-6 Alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1 -6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or through a or multiple R21 substitutions; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1 -6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl and H.

[0637] Embodiment 1-186. The compound of embodiment 1-185, wherein R3 is selected from carbocycle and heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted by one or more R10.

[0638] Embodiment 1-187. The compound of embodiment 1-186, wherein R3 is selected from: ,,,,,,, and, any of which is unsubstituted or substituted by one or more R10.

[0639] Embodiment 1-188. The compound of embodiment 1-185, wherein R3 is selected from C1-6 alkyl substituted by one or more R9.

[0640] The compound of embodiment 1-189. embodiment 1-188, wherein R3 is selected from: ,,,, and.

[0641] Embodiment I-190. The compound of embodiment I-185, wherein R3 is selected from C1-6 alkyl-N(R17)C(O)C1-6 alkyl N(R17)2.

[0642] Embodiment 1-191. The compound of any one of Embodiments 1-185 to 1-190, wherein R3 comprises an amine moiety.

[0643] Embodiment 1-192. The compound of embodiment 1-185, wherein R2 and R3 together form a 4-6 membered heterocyclic ring which is unsubstituted or substituted by one or more R11 with the atoms to which they are attached.

[0644] The compound of embodiment 1-193. embodiment 1-185, wherein R2 and R3 form a heterocyclic ring with the following structure together with the atoms they are connected to: ,,,,,,,,,,,, and, the Rings are unsubstituted or substituted with one or more R11.

[0645] Embodiment 1-194. The compound of embodiment 1-185, wherein R2 and R3 form a heterocyclic ring with the following structure together with the atoms to which they are attached: ,,,,,,,,, and.

[0646] Embodiment 1-195. The compound of any one of Embodiments 1-192 to 1-194, wherein R and R form a heterocyclic ring with the atoms to which they are attached, the heterocyclic ring (i) comprising additional nitrogen atoms and and / or (ii) substituted with a group comprising an amine moiety.

[0647] Embodiment 1-196. The compound of any one of Embodiments 1-185 to 1-195, wherein R1 is H.

[0648] Embodiment 1-197. The compound of any one of Embodiments 1-185 to 1-195, wherein R1 is -OR8.

[0649] The compound of embodiment 1-198. embodiment 1-197, wherein R8 comprises a 3-6 membered heterocycle that is unsubstituted or substituted by one or more R14.

[0650] Embodiment 1-199. The compound of any one of Embodiments 1-185 to 1-195, wherein R is selected from the group consisting of: ,,,,,,,,,,,, and.

[0651] Embodiment 1-200. The compound of any one of Embodiments 1-185 to 1-195, wherein R is selected from the group consisting of: ,,,,,,, and.

[0652] Embodiment 1-201. The compound of any one of Embodiments 1-185 to 1-195, wherein R1 is a 4-6 membered heterocyclic ring comprising a nitrogen atom, which is unsubstituted or modified by one or more R16 replacement.

[0653] The compound of embodiment 1-202. embodiment 1-201, wherein R1 is selected from: , and.

[0654] Embodiment 1-203. The compound of any one of Embodiments 1-185 to 1-202, wherein R6 is selected from the group consisting of: ,,,,,,,,,,, and.

[0655] The compound of embodiment 1-204. embodiment 1-203, wherein R6 is selected from: , , , and.

[0656] The compound of embodiment 1-205. embodiment 1-204, wherein R6 is: , and.

[0657] Embodiment 1-206. The compound of any one of Embodiments 1-185 to 1-205, wherein R4 is H.

[0658] Embodiment 1-207. The compound of any one of Embodiments 1-185 to 1-205, wherein R4 is halogen.

[0659] Embodiment 1-208. The compound of any one of Embodiments 1-185 to 1-207, wherein R7 is halogen.

[0660] Embodiment 1-209. A compound shown in any one of Tables 2-4, or a salt (eg, a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or Stereoisomers.

[0661] Embodiment 1-210. The compound of Embodiment 1-209, wherein the compound is shown in Table 2.

[0662] Embodiment 1-211. The compound of Embodiment 1-209, wherein the compound is shown in Table 3.

[0663] Embodiment 1-212. The compound of Embodiment 1-209, wherein the compound is shown in Table 4.

[0664] Embodiment 1-213. A pharmaceutical composition comprising the compound or its salt (such as a pharmaceutically acceptable salt) or an ester of any one of Embodiments 1-1 to 1-212 , tautomers, prodrugs, zwitterionic forms or stereoisomers, and pharmaceutically acceptable excipients.

[0665] Embodiment I-214. The compound of any one of Embodiments I-1 to I-212 or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, an amphoteric Ionic forms, or stereoisomers, which are useful as pharmaceutical agents.

[0666] Embodiment 1-215. The compound of Embodiment 1-214, wherein the agent is suitable for the prevention or treatment of a disease, disorder or condition that is ameliorated by inhibiting KRAS with a G12D mutation.

[0667] Embodiment 1-216. The compound of embodiment 1-214 or 1-215, wherein the agent is useful in the prevention or treatment of cancer.

[0668] Embodiment 1-217. The compound of Embodiment 1-216, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer and lung cancer.

[0669] Embodiment I-218. The compound of any one of Embodiments I-1 to I-212 or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, an amphoteric Ionic forms or stereoisomers, which are used in the treatment of a disease, disorder or condition.

[0670] Embodiment 1-219. The compound of Embodiment 1-218, wherein the disease, disorder or condition is cancer.

[0671] Embodiment 1-220. The compound of Embodiment 1-219, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer and lung cancer.

[0672] Embodiment 1-221. The compound of any one of Embodiments 1-218 to 1-220, wherein the compound is for use in the treatment of a disease, disorder or disorder in a subject in need thereof.

[0673] Embodiment I-222. The compound of any one of Embodiments I-1 to I-212 or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, an amphoteric Ionic forms, or stereoisomers, which are used in the manufacture of medicaments.

[0674] Embodiment 1-223. The compound of Embodiment 1-222, wherein the agent is suitable for the prevention or treatment of a disease, disorder or condition that is ameliorated by inhibiting KRAS with a G12D mutation.

[0675] Embodiment 1-224. The compound of Embodiment 1-222 or 1-223, wherein the agent is useful in the treatment of cancer.

[0676] Embodiment 1-225. The compound of Embodiment 1-224, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer and lung cancer.

[0677] Embodiment 1-226. A method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-1 to 1-212, or a salt thereof (e.g., pharmaceutically acceptable accepted salts), esters, tautomers, prodrugs, zwitterionic forms or stereoisomers.

[0678] Embodiment 1-227. The method of Embodiment 1-226, wherein the individual has a disease, disorder or condition that is improved by inhibiting KRAS with a G12D mutation.

[0679] Embodiment 1-228. The method of Embodiment 1-226 or 1-227, wherein the individual has cancer.

[0680] Embodiment 1-229. The method of Embodiment 1-228, wherein the individual was previously diagnosed with the cancer.

[0681] Embodiment 1-230. The method of Embodiment 1-228, wherein the individual has previously undergone a treatment regimen for the cancer.

[0682] Embodiment 1-231. The method of embodiment 1-228, wherein the subject has previously been in remission for the cancer.

[0683] Embodiment 1-232. The method of any one of Embodiments 1-228 to 1-230, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

[0684] Embodiment 1-233. The method of any one of Embodiments 1-226 to 1-232, wherein the compound, or a salt, ester, tautomer, prodrug, zwitterionic form or stereoisomer thereof The system is administered in combination with additional therapeutic agents.

[0685] Embodiment I-234. The compound of any one of Embodiments I-1 to I-212 or a salt thereof (such as a pharmaceutically acceptable salt), an ester, a tautomer, a prodrug, an amphoteric Use of ionic forms or stereoisomers in the manufacture of medicaments for the treatment of cancer.

[0686] Embodiment 1-235. The use of Embodiment 1-234, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

[0687] Embodiment 1-236. A method comprising making the KRAS protein and any one of the compounds or salts (such as pharmaceutically acceptable salts) or esters thereof in Embodiments 1-1 to 1-212 , tautomers, prodrugs, zwitterionic forms or stereoisomers.

[0688] Embodiment 1-237. The method of Embodiment 1-236, wherein contacting the KRAS protein with the compound modulates KRAS.

[0689] Embodiment 1-238. The method of Embodiment 1-236 or 1-237, wherein the KRAS protein has a G12D mutation.

[0690] Embodiment 1-239. The method of any one of Embodiments 1-236 to 1-238, wherein the KRAS protein is in an active state.

[0691] Embodiment 1-240. The method of any one of Embodiments 1-236 to 1-238, wherein the KRAS protein is in an inactive state.

[0692] Embodiment 1-241. The compound of any one of Embodiments 1-1 to 1-212 or a salt thereof (eg, a pharmaceutically acceptable salt).

[0693] Embodiment II-1. A compound represented by formula I: (I) or its salt (such as a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form or Stereoisomers, wherein: R1 is selected from -OR8, a 4-6 membered heterocyclic ring containing a nitrogen atom, and H, wherein the heterocyclic ring is unsubstituted or substituted by one or more R16; R2 is selected from H and C1- 6 alkyl; R3 is selected from C1-6 alkyl, carbocycle and heterocycle, wherein any C1-6 alkyl is substituted by one or more R9, and wherein the carbocycle or heterocycle is unsubstituted or substituted by one or A plurality of R10 substitutions; or R2 and R3 form a heterocyclic ring unsubstituted or substituted by one or more R11 with the atoms they are connected to; R4 is selected from H, halogen, -OR12, -CN, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, 3-6 membered carbocycle and 3-6 membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbon The ring and heterocycle are unsubstituted or substituted by one or more R14; R5 is selected from halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-6 members Carbocycle and 3-6-membered heterocycle, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13, and any carbocycle and heterocycle is unsubstituted or substituted by one or more R14; R6 It is a bicyclic heteroaryl group substituted by one or more R15; R7 is selected from halogen, -OR12, -CN and H; R8 is selected from heterocycle and alkyl heterocycle, either of which is unsubstituted or via a or multiple R16 substitutions; each R9 is independently selected from -N(R17)2, -N(R17)C(O)C1-6 alkyl and -OR17, wherein any C1-6 alkyl is unsubstituted or One or more R18 substitutions; each R10 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl )N(R19)2, -(C1-6alkyl)C(O)N(R19)2,-C(NR19)NR19CN and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or One or more R20 substitutions; each R11 is independently selected from -N(R19)2, -C(O)R19, -C(O)N(R19)2, -C(O)(C1-6 alkyl )N(R19)2, -(C1-6alkyl)C(O)N(R19)2,-C(NR19)NR19CN and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or One or more R20 substitutions; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl and H, wherein any C1-6 alkyl or C2-6 alkenyl is unsubstituted or through one or more R13 is substituted; each R13 is independently selected from -OR22, -CN, -N(R22)2 and halogen; each R14 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1- 6 alkyl is unsubstituted or substituted by one or more R13; each R15 is independently selected from halogen, N(R12)2 and C1-6 alkyl, wherein any C1-6 alkyl is unsubstituted or substituted by one or Multiple R13 substitutions; each R16 is independently selected from halogen, -N(R12)2, C1-6 alkyl and -OR12, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R13; each R17 is independently selected from C1-6 alkyl and H; each R18 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R19 is independently is selected from C1-6 alkyl and H, wherein any C1-6 alkyl is unsubstituted or substituted by one or more R21; each R20 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; each R21 is independently selected from -OH, -OC1-6 alkyl, -CN, -NH2, -NHC1-6 alkyl and halogen; and each R22 is independently Selected from C1-6 alkyl, C2-6 alkenyl and H.

[0694] Embodiment II-2. The compound of Embodiment II-1, wherein R1 is -OR8.

[0695] Embodiment II-3. The compound of Embodiment II-2, wherein R8 is a heterocycle.

[0696] The compound o...

Claims

1. A compound or a pharmaceutically acceptable salt thereof represented by the formula ID', (ID'), wherein: R1 series; R2 and R3, together with the atoms they are attached to, form 4-6 member heterocycles selected from the following: , ... R24, R25 and R26 are each independently selected from H, halogens, -OR12 and C1-6 alkyl; and Ra and Rb are each independently selected from halogens, C1-6 alkyl, -OR12 and H, wherein the C1-6 alkyl is unsubstituted or substituted by one or more R13.

2. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R1 is selected from: , , , , and.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is a compound.

4. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R2 and R3 together with the atoms to which they are attached form a 4-6 member heterocycle selected from the following: , , , , , , , , and.

5. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R2 and R3 together with the atoms to which they are attached form a 4-6 member heterocycle selected from: , , , , and.

6. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R2 and R3 are formed together with the atoms to which they are attached.

7. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is...

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is a halogen.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is an unsubstituted or C1-6 alkyl group substituted with one or more R13s.

10. The compound of claim 9 or its pharmaceutically acceptable salt thereof, wherein each R13 is independently a halogen.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is a C1-6 alkyl group substituted with one or more halogens.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 is a halogen.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 is -CN.

14. A compound or a pharmaceutically acceptable salt thereof represented by the formula ID', (ID'), wherein: R1 series; R2 and R3 together with the atoms they are attached to form heterocycles selected from the following: , , , , and; R4 series H; R5 series halogen or C1-6 alkyl substituted with one or more halogens; R7 series halogen or -CN; and Ra and Rb are each independently selected from halogens, C1-6 alkyl and H.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: , , , and.

16. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R1 is a group.

17. The compound of claim 14 or its pharmaceutically acceptable salt, wherein R2 and R3 are formed together with the atoms to which they are attached.

18. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R5 is a C1-6 alkyl group substituted with one or more halogens.

19. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R7 is a halogen.

20. A compound or a pharmaceutically acceptable salt thereof represented by the following structure.

21. A pharmaceutical composition comprising a compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. Use of a compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease, symptom or ailment of an individual.

23. For the purposes of claim 22, wherein the individual suffers from a disease, condition or disorder that is improved by suppressing KRAS with a G12D mutation.

24. For the purposes of request item 22, where the individual has cancer.

25. For the purposes of request 23, where the individual has cancer.

26. As requested in claim 24, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer and lung cancer.

27. As requested in claim 25, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer and lung cancer.

28. As claimed in claim 24, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

29. As claimed in claim 25, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

30. As claimed in claim 23, wherein the KRAS protein is in an active state.

31. As claimed in claim 23, wherein the KRAS protein is in an inactive state.

32. An in vitro method comprising contacting a KRAS protein with a compound of any one of claims 1 to 20 or a medically acceptable salt thereof.

33. The method of claim 32, wherein contacting the KRAS protein with the compound modulates KRAS.

34. The method of claim 32, wherein the KRAS protein has a G12D mutation.

35. The method of claim 33, wherein the KRAS protein has a G12D mutation.

36. The method of claim 32, wherein the KRAS protein is in an active state.

37. The method of claim 33, wherein the KRAS protein is in an active state.

38. The method of claim 32, wherein the KRAS protein is in an inactive state.

39. The method of claim 33, wherein the KRAS protein is in an inactive state.

40. A compound selected from the following table or a pharmaceutically acceptable salt thereof: .