Fused azoles as p53 mutant stabilizer

Abstract

The present disclosure relates to compounds and methods to restore wild-type function of p53 mutants and to treat proliferative disorders or cancers associated with p53 mutation. Formula (O)

Description

FUSED AZOLES AS P53 MUTANT STABILIZER CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No.63 / 558,093, filed February 26, 2024, the disclosure of which is hereby incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure in some aspects relates generally to compounds that bind to a mutant p53 protein and are capable of modulating the conformation thereof. The present disclosure in some aspects relates generally to method of restoring wild-type function of p53 mutants and treating proliferative disorders, such as cancers associated with p53 mutation. BACKGROUND

[0003] The transcription factor p53 functions as a tumor suppressor and is one of the most potent tumor suppressors in the cell, as it regulates a plethora of intracellular metabolic pathways, including DNA damage repair, apoptosis, and senescence. The gene encoding the p53 protein is the most frequently altered gene in human tumors. The loss of transcriptional functions leading to the deactivation of intrinsic tumor suppressive responses associated with wild-type (WT) p53 is the primary outcome of p53 mutations, and is a hallmark of most cancers.

[0004] Y220C is the most common mutation outside the DNA-binding surface and is associated with over 100,000 new cancer cases per year worldwide. The hydrophobic and “druggable” nature of the Y220C pocket offers a fruitful opportunity for targeting using small-molecule stabilizers. However, small molecules with high potency of binding to the Y220C mutation and restoring the wild-type function of p53 remain an unmet need. The present disclosure addresses this and other needs. SUMMARY

[0005] In some embodiments of the method described herein, the compound is of any one of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II),Table 1, or Table 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the forgoing Formulae are as defined herein or any variation thereof.

[0006] In some embodiments, provided herein is a pharmaceutical formulation comprising a compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A- I-3), Formula (A-I-4),Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, provided herein is a formulation comprising a compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or a pharmaceutically acceptable salt thereof, wherein the composition is sterile.

[0007] In yet another aspect, provided herein is a composition comprising a mutant p53 protein and a p53 stabilizer having a covalent bond to the mutant p53 protein, wherein the mutant p53 protein comprises a Y220C mutation, and the covalent bond is formed between a -CN group of the p53 stabilizer and the cysteine at position 220 in the mutant p53 protein. In some embodiments of the foregoing, the mutant p53 protein has greater wild-type function compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments of the foregoing, the mutant p53 protein has a greater wild-type conformation compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments of the foregoing, the p53 stabilizer is a compound of any one of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I- 3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or a stereoisomer thereof, or a salt (e.g., a pharmaceutically acceptable salt) thereof. DETAILED DESCRIPTION

[0008] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that the description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.I. Definition

[0009] For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.

[0010] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0011] “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-C10means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20alkyl”), having 1 to 10 carbon atoms (a “C1-C10alkyl”), having 6 to 10 carbon atoms (a “C6-C10alkyl”), having 1 to 6 carbon atoms (a “C1-C6alkyl”), having 2 to 6 carbon atoms (a “C2-C6alkyl”), or having 1 to 4 carbon atoms (a “C1-C4alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0012] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20alkylene”), having 1 to 10 carbon atoms (a “C1-C10alkylene”), having 6 to 10 carbon atoms (a “C6-C10alkylene”), having 1 to 6 carbon atoms (a “C1-C6alkylene”), 1 to 5 carbon atoms (a “C1-C5alkylene”), 1 to 4 carbon atoms (a “C1-C4alkylene”) or 1 to 3 carbon atoms (a “C1-C3alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.

[0013] “Haloalkyl”, as used herein refers to the same residues as alkyl, but having at least one (e.g., 1, 2, 3, 4, 5, or 6) hydrogens replaced with halogen, including F, Cl, Br, and I. When more than one hydrogen is replaced by halogen, each halogen is independently selected from F, Cl, Br, and I. For example, an alkyl can be substituted with one F group and one Br group, with two F groups, with one Cl group and one Br group, or with one Br group and one I group. Examples of haloalkyl include trifluoromethyl, difluoromethyl, 2- fluoroethyl, penta-fluoroethyl, and 3-bromo-1-fluoro-butyl.

[0014] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10means two to ten carbon atoms). An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20alkenyl”), having 6 to 10 carbon atoms (a “C6-C10alkenyl”), having 2 to 8 carbon atoms (a “C2-C8alkenyl”), having 2 to 6 carbon atoms (a “C2-C6alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4alkenyl”). Alkenyl groups also include dienes, including cumulated dienes (i.e., two C=C share a common carbon), conjugated dienes (i.e., two conjugated C=C separated by a single bond), and unconjugated dienes (i.e., two C=C separated by two or more single bonds). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2- methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3- dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, 1,2-propadiene, 2- methyl-1,3-butadiene, and the like.

[0015] “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a “C2-C20alkenylene”), having 2 to 10 carbon atoms (a “C2-C10alkenylene”), having 6 to 10 carbon atoms (a “C6-C10alkenylene”), having 2 to 6 carbon atoms (a “C2-C6alkenylene”), 2 to 4 carbon atoms (a “C2-C4alkenylene”) or 2 to 3 carbon atoms (a “C2-C3alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-1-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-1-enylene (-CH=CH-(CH2)3CH2-), and the like.

[0016] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C2-C10means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2- C20alkynyl”), having 6 to 10 carbon atoms (a “C6-C10alkynyl”), having 2 to 8 carbon atoms (a “C2-C8alkynyl”), having 2 to 6 carbon atoms (a “C2-C6alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4alkynyl”). Examples of alkynyl groups include, but are not limited to, groupssuch as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2- ynyl, but-3-ynyl, and the like.

[0017] “Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkynylene groups are those having 2 to 20 carbon atoms (a “C2-C20alkynylene”), having 2 to 10 carbon atoms (a “C2-C10alkynylene”), having 6 to 10 carbon atoms (a “C6-C10alkynylene”), having 2 to 6 carbon atoms (a “C2-C6alkynylene”), 2 to 4 carbon atoms (a “C2-C4alkynylene”) or 2 to 3 carbon atoms (a “C2-C3alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH2-), and the like.

[0018] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 14 annular carbon atoms, from 3 to 13 annular carbon atoms, or from 3 to 6 annular carbon atoms. A particular cycloalkyl is a cyclic hydrocarbon having from 3 to 14 annular carbon atoms (a "C3-C14cycloalkyl"), 3 to 13 annular carbon atoms (a "C3-C13cycloalkyl"), having 3 to 6 annular carbon atoms (a “C3-C6cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4cycloalkyl"). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0019] “Cycloalkylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro, or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A particular cycloalkylene is a cyclic hydrocarbon having from 3 to 4 annular carbon atoms (a “C3-C14cycloalkylene”), from 3 to 13 annular carbon atoms (a “C3-C13cycloalkylene”), having 3 to 6 carbon atoms (a “C3-C6cycloalkylene”), or having from 3 to 4 annular carbon atoms (a “C3-C4cycloalkylene”). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other. For example, cyclopropylene mayinclude 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2- cyclopropylene), or a mixture thereof.

[0020] “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C3-C10means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A particular cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 13 annular carbon atoms (a “C3-C13cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0021] “Cycloalkenylene” as used herein refers to the same residues as cycloalkenyl, but having bivalency.

[0022] “Aryl” or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-C14aryl”). In some instances, all rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring. An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

[0023] “Arylene” as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a “C6-C14arylene”).

[0024] “Heteroaryl” as used herein refers to an aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), provided the entire group is aromatic. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatomsindependently selected from nitrogen, oxygen and sulfur. In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0025] “Heteroarylene” as used herein refers to the same residues as heteroaryl, but having bivalency.

[0026] “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or a partially unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings (e.g., fused rings, bridged rings, spiro rings, or any conbiantion thereof), and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, bridged, or spiro, or any combination thereof, but excludes heteroaryl groups. A heterocyclyl group may comprise multiple rings, wherein at least one of the condensed rings is not aromatic, and the remaining ring(s) can be aromatic or non-aromatic. When a heterocyclyl group comprises at least one ring that is aromatic and at least one ring that is non-aromatic, the annular heteroarom(s) may be present in an aromatic ring, in a non- aromatic ring, or in both aromatic and non-aromatic rings. A heterocyclyl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heterocyclyl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. A heterocyclyl group may be connected to the parent structure via either a heteroatom or a carbon atom. Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12- membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6- membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0027] “Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bivalency. In some variations, heterocyclylene comprises more than one ring provided that at least one ring is non-aromatic, and a heterocyclylene may be connected to the parent structure at two aromatic ring positions, at two non-aromatic ring positions, or at an aromatic ring position and at a non-aromatic ring position.

[0028] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (–OCF3).

[0029] “Oxo” refers to the moiety =O.

[0030] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In some embodiments, an optionally substituted group has more than one substituents, wherein each substituent is independently selected. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted. It should be understood that substitution as used herein, unless otherwise specified, encompasses the scenario where the substituent(s) replaces a hydrogen, and may also encompasses the scenario where the substitution(s) does not replace a hydrogen. For example, in someembodiments, substitution encompasses the formation of N-oxide, S-oxide, and quatemized N. For example, heterocycle substituted with oxo group may encompass groups such as

[0031] It is understood that an optionally substituted moiety can be substituted with more than five substituents, if permitted by the number of valences available for substitution on the moiety. For example, a propyl group can be substituted with seven halogen atoms to provide aperhalopropyl group. The substituents may be the same or different. Where there are multiple substituents within a moiety or compound, it is to be understood that each substituent may be selected independently of each other substituent.

[0032] Unless clearly indicated otherwise, ‘"an individual’’ or ‘"a subject” as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.

[0033] zXs used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g, preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of cancer. The methods provided herein contemplate any one or more of these aspects of treatment.

[0034] In certain instances, the terms "prevention", "prophylaxis" and "preclusion" are used synonymously and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder (e.g.. a proliferative disorder), a symptom or a health problem, or a development or advancement of such states and / or the symptoms of such states. In certain instances, prevention means delaying the development of a disease or any symptom thereof. For example, prevention of a proliferative disorder means to delay, defer, hinder, slow, retard, stabilize, and / or postpone development ofthe disorder or any symptom thereof. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant prevention or delay can, in effect, result in that the individual does not develop the disease. A method that prevents development of a proliferative disorder (e.g., cancer) is a method that reduces probability of disease development in a given time frame and / or reduces the extent of the disorder in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. Cancer development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence, and onset. The treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.

[0035] The term “effective amount” as used herein, refers to a sufficient amount of at least one agent being administered to achieve a desired result, e.g., to induce apoptosis in at least one abnormally proliferating cell or to relieve to some extent one or more symptoms of a disease or condition being treated. In certain instances, the method is in vitro, and the desired result may comprise certain desired alteration of cells or biological processes. In certain instances, the method is in vivo, and the result may comprise a reduction and / or alleviation of the signs, symptoms, or causes of a disease, such as cancer. In certain instances, the result is a death of or decrease in the growth of at least one abnormally proliferating cell, e.g., a cancer cell. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0036] In certain instances, an “effective amount” is considered in the context of therapeutical uses and may be optionally referred to as “therapeutically effective amount”. A “therapeutically effective amount” refers to an amount of the compound or the composition comprising a compound or salt thereof as set forth herein sufficient to produce a desired therapeutic outcome and / or required to provide a clinically significant decrease in a disease. An appropriate “effective” or “therapeutically effective” amount in any individual case isdetermined using any suitable technique, such as a dose escalation study. In various embodiments, an effective amount or a therapeutically effective amount of the compound may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of a tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to ameliorate, palliate, lessen, and / or delay one or more of symptoms of cancer.

[0037] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

[0038] As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH- dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

[0039] As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have in some embodiments met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0040] “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0041] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound provided herein as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0042] Unless otherwise stated, "substantially pure" intends a composition that contains no more than 10% impurity, such as a composition comprising less than 9%, 7%, 5%, 3%, 1%, 0.5% impurity.

[0043] It is understood that aspects and embodiments described herein as “comprising’’ include “consisting of' and “consisting essentially of' embodiments.

[0044] In the descriptions herein (e.g., compound of Formula (O), Formula (A-I). Formula (A-I-1), Formula (A-I-2). Formula (A-I-3), Formula (A-I-4), Fonnula (A-Il). Formula (A-III), Formula (B), Fonnula (B-I), and Fonnula (B-II), Table 1, or Table 2) it is understood that every description, variation, embodiment or aspect of a. moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, eveiy description, variation, embodiment or aspect provided herein with respect to R1of Fonnula (O) may- be combined with eveiy description, variation, embodiment or aspect of R2of Formula (B) the same as if each and eveiy combination were specifically and indi vidually listed.

[0045] Provided herein are all salts of compounds referred to herein, such as pharmaceutically acceptable salts. Also provided herein are any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described. In some embodiment, the compounds provided herein may undergo tautomerization, and all the tautomers are also within the scope of the present invention. For example, in some embodiments, RNis H. and the compound of Formula (O) may undergo the below tautomerization:and both tautomers are emcompassed by the present invention.

[0046] In some embodiments, unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a. specific stereochemical form is depicted, it is understood that other stereochemical forms are also described and embraced by the disclosure. All forms of the compounds are also provided herein, such as crystalline or noncrystalline forms of the compounds. It is also understood that prodrugs, solvates and metabolites of the compounds are provided herein. Compositions comprising a compound described herein are also provided herein, such as a composition of substantially purecompound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds described herein in any ratio are also provided herein, including mixtures of two or more stereochemical forms of a compound in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.

[0047] The disclosure also includes isotopically-labeled and / or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I- 3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or variations thereof described herein, where one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, chlorine, such as2H,3H,11C,13C,14C13N,15O,17O,35S,18F,36Cl. Incorporation of heavier isotopes such as deuterium (2H or D) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances. As used herein, each instance of enrichment, substitution, or replacement of an atom with corresponding isotope of that atom encompasses isotopic enrichment levels of one of about: 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99,6%, 99.7%, 99.8%, 99.9%, or 100%, or a range between any two of the preceding percentages.

[0048] Isotopically-labeled compounds of the present disclosure can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically- labeled reagents in place of the corresponding non-labeled reagent.

[0049] It should be understood that the chemical structures, formulae, and descriptions set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. The descriptions of compounds are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would not be known to one of ordinary skill in the art as likely to be unstable underambient conditions, such as aqueous, neutral, and several known physiological conditions. In some embodiments, the substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene), unless otherwise specified, may be attached to any of the ring atoms (obeying the rules of chemical valency). When a ring is substituted with multiple substituents, unless otherwise specified, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may be independently selected and optionally be different. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the substitution positions on the ring, fused rings, or spirocyclic rings are not specified, the substituents (including, but not limited to, points of attachment to the remainder of the molecule or other substituents) may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with one or more substituent, unless otherwise specified, the substituent can be understood to replace the hydrogen, including the hydrogen on the heteroatom, while obeying the rules of chemical valency. II. Compounds Compounds of Formula (O)

[0050] In one aspect, provided herein is a compound of Formula (O): , or a salt thereof, wherein:A2is N or CR2; and A3is N or CR3; provided that no more than one of A2and A3is N; X is N or CR5;RNis H, D, C1-C3alkyl optionally substituted with one or more independently selected RN1, or C3-C5cycloalkyl optionally substituted with one or more halo; RN1is halo or cyclopropyl optionally substituted with one or more independently selected halo, R1and R4are independently selected from the group consisting of H, D, and halo, provided that when X is N, at least one of R1and R4is halo; one of R2and R3is -N(Ra)-L1-R2a, -N(Ra)-C(O)-R2b, -N(Ra)-C(O)-N(Ra)-R2c, -N(Ra)-R2d, - N(R )- M5N(R )-R , -N(R )-M2M3L2R , -N(R )-M4M5C(O)-N(R )-R , -N(R )-M6M O-R2h, -C(O)-N(Ra)-(L3)n-R2i, -N(Ra)-M8-N(Ra)-L4-R2j, -N(Ra)-M9-N(Ra)-L5-C(O)-R2k, - N(R2l)-C(O)-N(Ra)-L6-R2m, or -N(Ra)-M10-R2n, R2ais 3- to 14-membered heterocyclyl, 5- to 6-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2bis 3- to 14-membered fully saturated heterocyclyl optionally substituted with one or more independently selected R20; R2cis 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2dis C3-C14cycloalkyl or 3- to 14-membered fully saturated heterocyclyl, each of which is optionally substituted with one or more independently selected R20; R2eis 3- to 14-membered heterocyclyl, C6-C12aryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2f, R2g, R2h, R2i, R2j, R2k, R2l, R2m, and R2n, at each occurrence, are independently 3- to 14-membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; wherein each R20is D, halo; -CN; oxo; -COORa; -N(Ra)2; -ORa; -O-(5- to 12- membered heteroaryl); -SO2Ra; -N(Ra)-C(O)-Ra; -N(Ra)-C(O)-N(Ra)2; -C(O)-N(Ra)2; -C(O)- N(Ra)-R20a; -C(O)-N(Ra)-L7-ORa; C1-C6alkyl optionally substituted with one or more independently selected -ORa, -C(O)ORa, or -SO2Ra; C6-C14aryl optionally substituted with one or more independently selected halo or -ORa; 5- to 14-membered heteroaryl optionally substituted with one or more independently selected halo or C1-C6alkyl; C3-C14cycloalkyloptionally substituted with one or more independently selected -OR8or -SO2R8; 3- to 14- membered heterocyclyl optionally substituted with one or more independently selected halo; or C2-C6alkynyl optionally substituted with one or more independently selected halo or - N(Ra)C(O)ORa; wherein R20ais C3-C8cycloalkyl optionally substituted with one or more halo; -CN; orthe other one of R2and R3, if present, is H. D, halo, -NO2, -C00R8, -C(O)-N(Ra)2, -N(R*)- C(O)-Ra, 5- to 14-membered heteroaryl, C1-C6alkyl optionally substituted with one or more independently selected -N(Ra)2or halo, or Cj.-C6cycloalkyl optionally substituted with one or more independently selected -N(Rr,')2or halo;R3, if present, is H, D, halo, C1-C6alkyl optionally substituted with one or more independently selected halo, or C3-C6cycloalkyl optionally substituted with one or more independently selected halo;L1, L2, L3, L4, L5, L6, and L7, at each occurrence, are independently C1-C6alkylene optionally substituted with one or more independently selected -OH, -CN, halogen, or C3-C6cycloalkyl; n is 0 or 1 ; M1, M2, M3, M4, M5, M6, M7, M8, M9, and M10, at each occurrence, are independently C3-C14cycloalkylene or 3- to 14-membered heterocyclylene, each of which is optionally substituted by one or more substituents independently selected from the group consisting of oxo, -CN, halo, -OH, -OD, C1-C6alkyl, C3-C6cycloalkyl, and -C(O)-N(Ra)2; and wherein Ra, at each occurrence, is independently H; D; C1-C6alkyl optionally substituted with one or more independently selected halogen, -OH, -OD, -O-(C1- C3alkyl), or oxo; or C3- C6cycloalkyl optionally substituted with one or more independently selected halogen, -OH, - OD, -O-(C1-C3alkyl), or oxo.

[0051] In some embodiments, R is H or D. hi some embodiments. RNis C1-C3alkyl or C3C5cycloalkyl, each of hich is optionally substituted. In some embodiments. Rxis C1-C3alkyd or C3-C5cycloalkyl, each of hich is optionally substituted with one, two, or three halo. In some embodiments, RNis C1-C3alkyl substituted with F. In some embodiments, RNis C1-C3alkyl substituted with three F. In some embodiments, R is -CH2CF3. In some embodiments, RNis C1-C3alkyl substituted with cyclopropyl. In some embodiments, RNis C3-C5cycloalkyl optionally substituted with one or more (e g.. one to five, one to three, one, two. or three)halo. In some embodiments, R is H or C1-C3alkyl optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected halo or cyclopropyl. In some embodiments, RNis C1-C3alkyl optionally substituted with one or more independently selected halo or cyclopropyl; or RNis C3-C5cycloalkyl optionally substituted with one or more halo. In some embodiments, RNis -CH2CF3, -CH3, -CH2CH3, -C(CH3)HCF3, -CH2CH2F, -CH2CHF2,

[0052] In some embodiments, one of R2and R5is -N(Ra)- L1-R2a, -N(Ra)-R2d, -N(R8)- M5- N(Ra)-R2c, -N(Ra)-M2-M3-L2-R2f, -N(Ra)-M4-M5-C(O)-N(Ra)-R28, -N(Ra)-M6-M7-O-R2h, - N(R8)-M8-N(Ra)-L4-R2j, N(Ra)-M9-N(R8)-L5-C(O)-R2k, or -N(Ra)-M10-R2n

[0053] In some embodiments, one of R2and R3is -N(Ra)-L1-R2a. In some embodiments, Rais II. hi some embodiments, Rais CH3. In some embodiments, R2ais 3- to 14-membered heterocyclyl. 5- to 6-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20. In some embodiments. R2ais 5- to 6-membered heteroaryl, or C3-C6cycloalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two. or three) independently selected R20. In some embodiments, R2ais 5- to 6-membered, heteroaryl or C3-C8cycloalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected halo, -CN, -NH2, phenyl, -CH2C(O)OCH2CH3, or C1-C6haloalkyl. In some embodiments, L1is C1-C6alkylene, such as C1-C3alkylene, methylene, ethylene, or propylene, each of which is unsubstituted. In some embodiments, L1is -CH2-. In some embodiments, one of R2and R5is.

[0054] In some embodiments, one of R2and R3is -N(Ra)-R2d. In some embodiments. Rais H. In some embodiments, Rais CH3. Tn some embodiments, R2dis C3-C14cycloalkyl or 3- to 14-membered fully saturated heterocyclyl, each of which is optionally substituted with one or more (e.g., one to fi ve, one to three, one, two, or three) independently selected R20. In some embodiments, R2dis 5- to 6-membered fully saturated heterocyclyl optionally substitutedwith one or more independently selected R20. In some embodiments, R2dis 5- to 6-membered fully saturated heterocyclyl optionally substituted with one. two, or three C1-C3alkyl. In some embodiments. R2° is C3-C14cycloalkyl (e.g. , cyclohexyl) optionally substituted with one, two, or three C1-C3alkyl. In some embodiments, one of R2and R3is

[0055] In some embodiments, one of R2and R3is -N(Ra)-R2d. In some embodiments, Rais H. In some embodiments, Rais CH.?. In some embodiments, R2dis C3-C14cycloalkyl optionally substituted with one or more (e.g., one to five, one to three, one. two, or three) independently selected R20. In some embodiments, R2dis Cj-C8cycloalkyl optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected -N(Ra)2, -N(Ra)-C(O)-Ra, or -N(Ra)-C(O)-N(Ra)z, wherein R8, at each occurrence, is independently H, D, or C1-C6alkyl optionally substituted with one or more (e.g., one to five, one to three, one. two, or three) independently selected halogen, -OH. -OD, or -O-(C1-C3alkyl). In some embodiments, R2dis C6-C8cycloalkyd optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected -NH2, -NH-C(O)- CH3, -N(CH3)-C(O)-CH3, or -NH-C(O)-NHCH3. In some embodiments, one of R2and R3is

[0056] In some embodiments, R2dis 5- to 8-membered heterocycle (e.g., 5- to 8-membered heterocycle comprising at one annular nitrogen) optionally substituted with one or more (e.g., one to five, one to three, one. two, or three) independently selected C1-C3alky] (e.g.. methyl).In some embodiments, one of R2and R3

[0057] In some embodiments, one of R2and R3is -N(Ra)-M1-N(Ra)-R2e. In some embodiments, Rais II. In some embodiments, R3is CH... In some embodiments, Rais - C(O)CH3. In some embodiments, one of R2and R3is -N(Ra)-M1-N(Ra)-R2e. wherein Rais H, CH3, or -C(O)CH3. In some embodiments, one of R2and R3is -NH-M1-NH-R2e, -NH-M1- N(CH.3)-R2e, or -NH-M1-M(C(O)CH3)-R2e. In some embodiments. M1is C5-C8cycloalkylene or 5- to 10-membered heterocyclyl ene. In some embodiments. M1is cyclohexylene. In some embodiments, R2eis 3- to 14-membered heterocyclyl, C6-C12aryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2eis 3- to 14-membered heterocyclyl (e.g., fully saturated heterocycle or partially unsaturated heterocycle), C6-C12aryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g.. one to five, one to three, one. two, or three) independently selected oxo; halo: 5 to 6-membered heterocyclyl; -OH; -OD; -N(Ra)-C(O)-Ra; -C(O)-N(Ra)2; C1-C6alkyl optionally substituted with one or more -OH or -OD; C6-C14aryl optionally substituted with one or more independently selected -ORa; or 5- to 14-membered heteroaryl optionally substituted with C1- C6alkyl. In some embodiments, R2eis 3- to 14-membered heterocyclyl (e.g., heterocycle comprising one annular O atom, or comprising one annul ar N atom) optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected oxo; halo; 5- to 6-membered heterocyclyl; -OH; -NH-C(O)CH3; -C(O)-NH2; C1-C3alkyl optionally substituted with one or more -OH; phenyl optionally substituted with one or moreindependently selected -OCH3; or 5- to 6-membered heteroaryl optionally substituted withCH3. Tn some embodiments, one of R2and R3is,

[0058] In some embodiments, one of R2and R3is -N(Ra)-M2-M3-L2-R2f. In some embodiments, Rais II. In some embodiments, Rais CHa. In some embodiments, Ma is C5-C8cycloalkyiene or 5- to 10-membered heterocyclylene. In some embodiments, Ma is C5-C6cycloalkylene or 5- to 6-membered heterocyclylene. In some embodiments, Ma is cyclohexylene. In some embodiments. Ma is C5-C8cycloalkyiene or 5- to 10-membered heterocyclylene. In some embodiments. Ma is C5-C6cycloalkyiene or 5- to 6-membered heterocyclylene. In some embodiments. Ma is 6-membered heterocyclylene. In some embodiments, Ma is cyclohexylene and Ma is 6-membered heterocyclylene. In some embodiments, R2fis 3- to 14-membered heterocyclyl, C6-Cia aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2fis 5- to 6-membered heteroaryl optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2fis unsubstituted 5- to 6-membered heteroaryl comprising at at least one annular nitrogen atom. In some embodiments. La is C1-C3alkylene, such as methylene.ethylene, or propylene. In some embodiments, L2is unsubstituted methylene. In some embodiments, one of R2and R' is

[0059] In some embodiments, one of R2and R3is -N(Ra)-M4-M5-C(O)-N(Ra)-R2g. In some embodiments, Rais H. In some embodiments, Rais CH3. In some embodiments, M4is C5-C8cycloalky lene or 5- to 10-membered heterocyclylene. In some embodiments, M4is C5-C6cycloalkyiene or 5- to 6-membered heterocyclylene. In some embodiments. M4is cyclohexylene. In some embodiments, M5is C5-C8cycloalkyiene or 5- to 10-membered heterocyclylene. In some embodiments, M5is 5- to 10-membered heterocyclylene. In some embodiments, M5is 6 to 8-membered heterocyclylene. In some embodiments, R2gis 3- to 14- membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g., one to live, one to three, one, two, or three) independently' selected R20. In some embodiments, R2gis 3- to 14-membered heterocyclyl or C3- C8cydoalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2gis 5- to 6-membered heterocyclyl or or C3-C6cydoalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) - OIL In some embodiments, R2gis 5- to 6-membered heterocyclyl or or C3-C6cydoalkyl. each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) -OH. In some embodiments, one of R2and R3is

[0060] In some embodiments, one of R2and R3is -N(Ra)-M6-M7-O-R2il. In some embodiments, Rais H. In some embodiments. Rais CH3. In some embodiments, Mr, is C5-C8cycloalkylene or 5- to 10-membered heterocyclylene. In some embodiments. Me is C5-C6cycloalkylene or 5- to 6-membered heterocyclylene. In some embodiments, Me is cyclohexylene. In some embodiments. M7is C3-C8cycloalkyiene or 5- to 10-membered heterocyclylene. In some embodiments, M7is 5- to 7-membered heterocyclylene. In some embodiments, M7is 5- to 6-membered heterocyclylene In some embodiments. R2his 3- to14-membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g., one io live, one to three, one, two, or three) independently selected R20. In some embodiments. R2his C6-C12aryl (e.g., phenyl) or 5- to 14-membered heteroary l (e.g.. 5- to 6-membered heteroary l). each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2his phenyl or pyridyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one. two, or three) independently selected C1-C3alkyl or halo. In some embodiments, one of R2and R3is

[0061] In some embodiments, one of R2and R3is -N(Ra)-M8-N(Ra)-L4-R2j. in some embodiments, Rais I L In some embodiments. Rais Cl L. In some embodiments, one of R2and R3is -NH-M8-N(Ra)-L4-R2i -N(Ra)-M8-N(CH3)-L4-R2j, or -NH-M8-N(CH3)-L4-R2i. In some embodiments, M8is C5-C8cycloalkylene or .5- to 10-membered heterocyclylene. In some embodiments, M8is C5-C6cycloalkylene or 5- to 6-membered heterocyclylene. In some embodiments, M8is cyclohexylene. In some embodiments, L4is C1-C3alkylene, (e.g., methylene, ethylene, branched or unbranched propylene). In some embodiments. L4is C1-C3alkylene (e.g., methylene) substituted with C3-C6cycloalkyl (e.g., cyclopentyl). In some embodiments, R2jis 3- to 14-membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g.. one to five, one to three, one. two. or three) independently selected R20. In some embodiments, R2jis C.6-C12aryl or 5- to 14-membered heteroawl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2jis phenyl optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) substituents selected, from C1-C3alkyl, CN, -O(C1-C3alky), -SO2(C1- C3alky), or C1-C3alky substituted with -OH. In some embodiments, R2jis 5- to 6-membered heteroaryl comprising at least one annular nitrogen or oxygen, whichis optionaliy substituted with one or more (e.g., one to five, one to three, one. two, or three) substituents selected from C1-C3alkyl, CN, -O( C1-C3alky). -SOstC1-C3alky), and C1-C3alky substituted with -OH. In some embodiments, one of R2and R3isIn someembodiments, one of R2and R3isor

[0062] In some embodiments, one of R2and R3is N(Ra)-M9-N(Ra)-L5-C(O)-R2k. In some embodiments, Rais H. In some embodiments, Rais CH3In some embodiments, one of R2and R3is NH-M9-N(Ra)-L5-C(O)-R2k, NH-M9-NH-L5-C(O)-R2k, or NH-M9-N(CH3)-L5-C(O)- R2k. In some embodiments, Mg is C5-C8cycloalkylene or 5- to 10-membered heterocyclylene. In some embodiments, Mg is C5-C6cycloalkylene or 5- to 6-membered heterocyclylene. In some embodiments. Mg is cyciohexylene. In some embodiments, L5is C1-C6alkylene, such as C1-C3alkylene, branched or unbranched propylene, branched or unbrached butylene, or branched or unbranched peniylene. In some embodiments, R2kis 3- to 14-membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2kis 3- to 14-membered heterocyclyl (e.g., 3- to 10-membered heterocyclyl. or 5- to 6-membered heterocyclyl) optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2kis unsubstituted 3- to 14-membered heterocyclyl (e.g., unsubstituted 3- to 10-membered heterocyclyl, or unsubstituted 5- to 6-membered heterocyclyl). In some embodiments, one of R2and R3is

[0063] In some embodiments, one of R2and R3is -N(Ra)-M10-R2n. In some embodiments, Rais H. In some embodiments. Rais CH3. In some embodiments. M10is C5-C8cycloalkylene or 5- to 10-membered heterocyclylene. In some embodiments, M10is C5-C6cycloalkylene or 5- to 6-membered heterocyclylene. In some embodiments, M10is cyciohexylene. In some embodiments, R2nis 3- to 14-membered heterocyclyl, C6-C12aryl, 5- to 14-memberedheteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2nis 3- to 14-membered heterocyclyl (e.g., 4- to 10-membered heterocyclyl, 4- to 6-membered heterocyclyl, or 7 to 10-membered heterocyclyl) or C3-C14cycloalkyl, each of which is optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, R2nis 3- to 14-membered heterocyclyl (e.g.. 4- to 10-membered heterocyclyl, 4- to 6-membered heterocyclyl, or 7 to 10-membered heterocyclyl) optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) substituents selected from halo, -Oil, C(O)NTl2, -C(O)NH( C1-C3alkylene)O-(C1-C3alkyl), phenyl, -CH2.SO2CH3, C3-C6cycloalkyl, -(C1-C3alkylene)O-(C1- C3alkyl), -O-(C1-C3alkyl), 5- to 6-membered heteroaryl optionally substituted with halo, and -C(O)-N(R3)-R20a, wherein R20sis C3-C8cycloalkyl optionally substituted with one or more(e.g., one to five, one to three, one, two, or three) halo; -CN; or. In some embodiments, one of R2and R3isIn some embodiments, one of R2and R3is

[0064] In some embodiments, one of R2and R3is -N(Ra)-C(O)-R2b, -N(Ra)-C(O)-N(Ra)- R20. -C(O)-N(Ra)-(L3)n-R2i, or -N(R2l)-C(O)-N(Ra)-L6-R2m.

[0065] In some embodiments, one of R2and R;is -N(Ra)-C(O)-R2b. In some embodiments, Rais H. In some embodiments, R3is CH3. In some embodiments, R2bis fully saturated 3- to 8-membered heterocyclyl (e.g., 4-. 5-. 6-, 7-, or 8-membered heterocyclyl) optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20.

[0066] In some embodiments, one of R2and R3is -N(Ra)-C(O)-N(Ra)-R2c. In some embodiments, Rais H. In some embodiments, Rais CH3. In some embodiments, R2cis 3- to 8-membered heterocyclyl (e.g.. 4-, 5-, 6-, 7-, or 8-membered heterocyclyl) optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20.

[0067] In some embodiments, one of R2and R3is -C(O)-N(Ra)-R2ior -C(O)-N(Ra)-L3-R21. In some embodiments, Ra:is H. in some embodiments, Rais CH3. In some embodiments, R2iis 3- to 14-membered heterocyclyl (e.g., 4-, 5-, 6-, 7~, or 8-membered heterocyclyl) optionally substituted, with one or more (e.g., one to five, one to three, one, two, or three) independently- selected R20.

[0068] In some embodiments, one of R2and R is -N(R2l)-C(O)-N(Ra)-L6-R2m. In some embodiments, Rais II. In some embodiments, Rais CH3. In some embodiments, R is 3- to 14-membered heterocyclyl (e.g., 4-, 5-, 6-. 7-, or 8-membered heterocyclyl) optionallysubstituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20and R2mis C6-C12aryl optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected R20. In some embodiments, one of R2and R3is10069] In some embodiments, one of R2and R3is: (i) -N(Ra)-L1-R2a. wherein L1is C1-C3alkylene; or (ii) N(Ra)-R2d. In some embodiments, one of R2and R?is

[0070] In some embodiments, one of R2and R3is: (i) -N(Ra)-M1-N(Rs)-R2c; (ii) -N(Ra)-M8- N(Ra)-L4-R2-l wherein M8is C3-C8cycloalkylene: Lr is C1-C3alkylene; and R2jis C6-C12. and or 5- to 14-membered heteroaiyd, each of which is optionally substituted with one or more independently selected R20; or (iii) N(Ra)-M9-N(Ra)-L5-C(O)-R2k, wherein M9is cyclohexylene: L5is C1-C6alkylene: and R2kis 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected R20. In some embodiments, one of R2,

[0071] In some embodiments, one of R2and R2is (i) -N(Ra)-M2-M3-L2-R2f. wherein R2fis 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R20; M2is cyclohexylene; M3is 5- to 6-membered heterocyclylene; and I.-2 is C1-C3alkylene; (ii) -N(Ra)-M4-M5-C(O)-N(Ra)-R28, wherein M4is cyclohexylene: M5is 5- to 8-membered heterocyclylene; and R2gis 3- to 14-membered heterocyclyl or C3-C8cycloalkyl, each of which is optionally substituted with one or more independently selected R20; or (iii ) -N(Ra)- Me-Mv-O-R2h, wherein Me is cyclohexylene; M7is 4- to 6-membered heterocyclylene; and R2his C6-C12aryl or 5- to 14-membered heteroaiyl, each of which is optionally substituted with one or more independently selected R20. In some embodiments, one of R2and R3is

[0072] In some embodiments, the other one of R2and R3. if present, is H, D. halo, -NO2, - COORa, -C(O)-N(Ra)2, -N(Ra)-C(O)-Ra, 5- to 14-membered heteroaryl, or C1-C6alkyl optionally substituted with one or more (e.g., one to five, one to three, one, two, or three) independently selected -X- Ra); In some embodiments, the other one of R2and R3, if present, is H or D. in some embodiments, the other one of R2and R3, if present, is H.

[0073] In some embodiments, R1is H, D, or halo. In some embodiments, R1is IT or D. In some embodiments, R1is halo. In some embodiments. R1is F. In some embodiments, R1is Br. In some embodiments, R4is H, D, or halo. In some embodiments. R4is H or D. In some embodiments, R4is F. In some embodiments, R4is Br. In some embodiments, R1and R4are each independently H or D. In some embodiments, R!and. R4are each H In some embodiments, one of R!and R4is H or D, and the other of R1and R4is Br. In some embodiments, R1is II and R4is Br. In some embodiments, R1is Br and R4is II. In some embodiments, one of R!and R4is H or D, and the other of R1and R4is I.

[0074] In some embodiments. X is N, one of R1and R2is halo and the other one of R1and R2is H or D. In some embodiments, X is N, R1is halo and R2is H or D. In someembodiments, X is CR5and at least one of R1and R4is halo. In some embodiments, X is CR5. one of R1and R4is halo and the other one of R1and R4is II or D.

[0075] In some embodiments, R5, if present, is H. D, halo, or C1-C6alkyl optionally substituted with one or more (e.g., one to five, one to three, one. two, or three) independently selected halo. In some embodiments, R5, if present, is II or D In some embodiments, R5, if present, is F. In some embodiments, R5, if present, is CF3. In some embodiments, R5, if present, is H, F, or CF3

[0076] In some embodiments. A2is N. In some embodiments, Azis CR2. In some embodiments, A3is N. In some embodiments, A3is CR3. In some embodiments. A2is CR2and A3is CR3. In some embodiments, A2is CR2and. A3is N. In some embodiments. A2is N and A3is CR3.

[0077] In some embodiments, X is N. In some embodiments, X is CR3. In some embodiments, X is N; one of R1and R4is halo; and the other of R1and R4is H.

[0078] In some embodiments, the compound is of Formula (A)or a salt thereof, wherein R1;, R1, A2, A3, and R4are as defined herein.

[0079] In some embodiments, the compound is of Formula (A-I)or a salt thereof, wherein RN, R1, A3, R2. and R4are as defined, herein.

[0080] In some embodiments, the compound, is of Formula (A-I-l)or a salt thereof, wherein RN, Ad, R2, and R4are as defined herein.

[0081] In some embodiments, the compound is of Formula (A-I-2)or a salt thereof, wherein R1, A3, R2, and R4are as defined herein.

[0082] In some embodiments, the compound is of Formula (A-I-3)or a salt thereof, wherein RN, A3, and R2are as defined herein.

[0083] In some embodiments, the compound is of Formula (A-I-4)or a salt thereof, wherein A3, and R2are as defined herein.

[0084] In some embodoments, the compound is of Formula (A-I), or a salt thereof, wherein at least one, two three, four or all of (i) to (v) applies:(i) h ' is H, or C1-C3alkyl substituted with one, two, or three halo or cyclopropyl;(ii) R1is halo;(iii) R2is -N(Ra)-L1-R2a, -N(Ra)-R2d. -N(Ra)- M5-N(Ra)-R2e. -N(Ra)-M2-M3-L2-R2f, -N(Ra)- M4-M5-C(O)-N(Ra)-R28, -M(Ra)-M6-M7-O-R2h, -N(Ra)-M8-N(Ra)-L4-R2j, N(Ra)-M9-N(Ra)-L5- C(O)-R2k, or -N(Ra)-M10-R2n;(iv) A3is N or CH; and(v) R’ is II or halo.

[0085] In some embodiments, the compound is of Formula (A-II)or a salt thereof, wherein RN, R1. A2. R-\ and R4are as defined herein.

[0086] In some embodiments, the compound is of Formula (A-I II )or a salt thereof, wherein RN, R1, R2. R3. and R4are as defined herein.

[0087] In some embodoments, the compound is of Formula (A-I), (A-I-l ), (A-I-2), (A-II), or (A-I1I), or a salt thereof, wherein at least one. two three, four or all of (i) to (v) applies:(i) RNIS H, -CH2CF3, or -Cl-h-cyclopropyl.(ii) RNis -CH2CF3;(iii) R1is halo; (iv) R2is -N(Ra)-L2a1-R,-N(Ra)-R2d, -N(Ra)- M5-N(Ra)-R2e, -N(Ra)-M2-M3-L2-R2f, -N(Ra)- M4-M5-C(O)-N(Ra)-R2g, -N(Ra)-M6-M7-O-R2h, -N(Ra)-M8-N(Ra)-L4-R2j, N(Ra)-M9-N(Ra)-L5- C(O)-R2k, or -N(Ra)-M10-R2n; and (v) R4is halo.

[0088] In some embodoments, the compound is of Formula (A-I), (A-I-1), (A-I-2), (A-II), or (A-III), or a salt thereof, wherein at least one, two three, four or all of (i) to (v) applies: (i) RNis H, -CH2CF3, or -CH2-cyclopropyl. (ii) RNis -CH2CF3; (iii) R1is halo; (iv) R2is -N(Ra)-R2d, -N(Ra)- M5-N(Ra)-R2e, -N(Ra)-M8-N(Ra)-L4-R2j, or -N(Ra)-M10-R2n; and (v) R4is halo.

[0089] In some embodiments, provided herein are compounds and pharmaceutically acceptable salts thereof described in Table 1. In some embodiments, the compound, or a salt thereof, is selected from the group consisting of the compounds of Table 1 and salts thereof.

[0090] In some embodiments, the compound is of Formula (B)or a salt thereof.

[0091] In some embodiments, the compound is of Formula (B-I)or a salt thereof.

[0092] In some embodoments, the compound is of Formula (B-I), or a salt thereof, wherein at least one, two three, four or ah of (i) to (v) applies:(i) RNis H, or C1-C3alkyl substituted with one, two. or three halo;(ii) R1is H or halo;(in) R3is -N(Ra)-L1-R2a, -N(Ra)-R2d. -N(Ra)- M5-N(Ra)-R2e, -N(Ra)-M2-M3-L2-R2f, -N(Ra)- M4-M5-C(O)-N(Ra)-R2g, -N(Ra)-M6-M7-O-R2\ -N(R3)-M3-N(Ra)-U-R9, N(Ra)-M9-N(R8)-L3- C(O)-R2k, or -N(Ra)-M10-R2n;(iv) R4is H or Br; and(v) R5is H or F.

[0093] In some embodoments, the compound is of Formula (B-I), or a. salt thereof, wherein at least one, two three, four or all of (i) to (v) applies:(i) R is H, or C1-C3alkyl substituted with one, two, or three fluoro;(ii) R!is H or Br;(hi) R3is -N(Ra)-R2dor -N(R3)-M10-R2n,(iv) R4is H or Br; and(v) R' is H or F.

[0094] In some embodiments, the compound is of Formula (B-II), or a salt thereof.

[0095] In some embodoments, the compound is of Formula (B-II), or a salt thereof, wherein at least one, two three, four or all of (i) to (v) applies: (i) RNis H, or C1-C3alkyl substituted with one, two, or three halo; (ii) R1is H or halo; (iii) R3is -N(Ra)-L1-R2a, -N(Ra)-R2d, -N(Ra)- M5-N(Ra)-R2e, -N(Ra)-M2-M3-L2-R2f, -N(Ra)- M4-M5-C(O)-N(Ra)-R2g, -N(Ra)-M6-M7-O-R2h, -N(Ra)-M8-N(Ra)-L4-R2j, N(Ra)-M9-N(Ra)-L5C(O)-R2k, or -N(Ra)-M10-R2n; (iv) R4is H or Br; and (v) R5is H or F.

[0096] In some embodoments, the compound is of Formula (B-II), or a salt thereof, wherein at least one, two three, four or all of (i) to (v) applies: (i) RNis H, or C1-C3alkyl substituted with one, two, or three fluoro; (ii) R1is H or Br; (iii) R3is -N(Ra)-R2dor -N(Ra)-M10-R2n; (iv) R4is H or Br; and (v) R5is H or F.

[0097] In some embodiments, provided herein is compound X:or a salt thereof. In some embodiments, the salt is a. pharmaceutically acceptable salt.

[0098] In some embodiments, provided, herein are compounds and pharmaceutically acceptable salts thereof described in Table 2. In some embodiments, the compound, or a salt thereof, is selected from the group consisting of the compounds of Table 2 and salts thereof.Table 278

[0099] In some embodiments, the compound, or a salt thereof, is selected from the group consisting of the compounds of Table 1 and Table 2, and salts thereof.

[0100] All the compounds described herein or a pharmaceutically acceptable salt thereof, can be used in the methods provided herein. The methods can be in vitro methods, such as in vitro methods of administering a compound to cells for screening purposes and / or for conducting quality control assays. The methods can also be in vivo methods, such as in vivo methods of administering a compound to a subject in need thereof for treating certain disorders. III. Method of Use

[0101] Certain bicyclic compounds containing a nitrile have been found to be effective in binding to p53 proteins having a Y220C mutation, and these compounds may be useful in stabilizing the protein and in treating conditions associated with this mutation. In one aspect, provided herein are methods comprising contacting a mutant p53 protein with an effective amount of a compound of Formula (O) as described herein. p53 Protein

[0102] The p53 protein, a tumor suppressor, is an amino acid transcription factor that can regulate cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage. P53 protein has various mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. Due to the critical role of p53 protein in tumor suppression, p53 protein is inactivated in almost all cancers either by direct mutation or through perturbation of associated signaling pathways involved in tumor suppression. The presence of certain p53 protein mutations in several types of human cancer can correlate with less favorable patient prognosis.

[0103] In an unstressed cell, p53 protein levels are maintained at low levels via the interaction of p53 protein with Mdm2, an E3 ubiquitin ligase, and Mdm2 can target p53 protein for degradation by the proteasome. Under stress conditions, the interaction between Mdm2 and p53 protein is disrupted, and p53 protein accumulates. The critical event leading to the activation of p53 protein is phosphorylation of the N-terminal domain of p53 by protein kinases, thereby transducing upstream stress signals. The phosphorylation of p53results in a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors. The activation of p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair. P53 protein can activate proteins involved in the above pathways including, for example, Fas / Apo, KILLER / DRS, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21 (WAFl). Additionally, p53 can repress the transcription of a variety of genes including, for example, c-MYC, Cyclin B, VEGF, RAD51, and hTERT.

[0104] Each chain of the p53 protein tetramer is composed of several functional domains including the transactivation domain (amino acids 1-100), the DNA-binding domain (amino acids 101-306), and the tetramerization domain (amino acids 307-355), which are highly mobile and largely unstructured. Most p53 protein mutations related to proliferative disorders are located in the DNA-binding core domain of the protein, which contains a central β- sandwich of anti-parallel β-sheets that serves as a basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two β-turn loops, L2 and L3, which are stabilized by a zinc ion, for example, at Arg175 and Arg248, and a loop-sheet-helix motif. Altogether, these structural elements form an extended DNA-binding surface that is rich in positively- charged amino acids, and makes specific contact with various p53 protein response elements.

[0105] Due to the prevalence of p53 protein mutations in many types of cancer, the reactivation of wild type p53 protein function in a cancerous cell can be an effective therapy. Mutations in p53 located in the DNA-binding domain of the protein or periphery of the DNA-binding surface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. P53 mutations that can abrogate the activity of p53 include, for example, Rl75H, Y220C, G245S, R248Q, R248W, R273H, and R282H. These p53 protein mutations can either distort the structure of the DNA- binding site or thermodynamically destabilize the folded protein at body temperature. Without being bound by theory, wild-type function of p53 mutants can be recovered by binding of the p53 protein mutant to a compound that can shift the folding-unfolding equilibrium towards the folded state, thereby reducing the rate of unfolding and destabilization. With the wild-type function of p53 protein recovered, downstream targets involved in tumor suppression can be further activated.Restore wild-type function of p53 mutants

[0106] In one aspect, provided herein is a method of modulating the conformation of a mutant p53 protein. In some embodiments, provided herein is a method of restoring wild-type activity of a mutant p53 protein including, for example, DNA binding function and activation of downstream targets involved in tumor suppression, wherein the method comprises selectively binding a compound described herein to the p53 mutant. In some embodiments, before contacted with the compounds described herein (e.g., a compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X), the p53 mutant has a conformation that is not pro-apoptotic, and the compound described herein can bind to the binding site on the p53 mutant and modulate the conformation of the p53 mutant to a form that is pro-apoptotic. In some embodiments, the modulation of the conformation of the p53 mutant comprises forming a covalent bond between the compounds provided herein (e.g., a compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X) and the p53 mutant. In some embodiments, the p53 mutant is Y220C. In some embodiments, the method of modulating the conformation of a mutant p53 protein comprises contacting the mutant p53 protein with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), is as defined herein. In some embodiments, the method of restoring wild-type function of a mutant p53 protein comprises contacting the mutant p53 protein with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula(A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), is as defined herein.

[0107] In some embodiments, provided herein is a method of binding a compound described herein to a p53 protein containing a Y220C mutation. In some embodiments, the compound described herein selectively binds to (e.g., has a higher binding affinity for) a p53 protein containing a Y220C mutation over a p53 protein that lacks the Y220C mutation. In some embodiments, the compound described herein has higher binding affinity for the Y220C residue on a p53 protein over other residues on the protein. In some embodiments, the compound described herein has higher binding affinity for the cysteine at position 220 in a p53 Y220C mutant protein compared to other cysteine residues in the protein. In some embodiments, provided herein is a method of stabilizing the Y220C mutant, optionally to reduce the likelihood of denaturation of the protein at body temperature with a compound provided herein. The Y220C mutant is a temperature sensitive mutant, which binds to DNA at lower temperature and is denatured at body temperature. Located in the periphery of the p53 β-sandwich connecting β-strands S7 and S8, the aromatic ring of Y220 is an integral part of the hydrophobic core of the β-sandwich. The Y220C mutation can be highly destabilizing, due to the formation of an internal surface cavity. In some embodiments, the compounds described herein can bind to and occupy this surface crevice to stabilize the sandwich, thereby restoring wild-type p53 DNA-binding activity.

[0108] In some embodiments, the method comprises determining the ability of a compound described herein to bind and stabilize mutant p53. In some embodiments, assays can be employed to detect, for example, a conformational change in the p53 mutant or activation of wild-type p53 targets. Conformational changes in p53 can be measured by, for example, differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC), nuclear magnetic resonance spectrometry (NMR), or X-ray crystallography. Additionally, antibodies specific for the wild type of mutant conformation of p53 can be used to detect a conformational change via, for example, immunoprecipitation (IP), immunofluorescence (IF), or immunoblotting.

[0109] In some embodiments, provided herein is a method of reactivating the transcriptional activity of p53. In some embodiments, the method is to activate downstream targets in the p53 signaling cascade. In some embodiments, the method is to activate p53 effector proteins. In some embodiments, the potency and efficacy of the compounds described herein in reactivating the transcriptional activity of p53 can be measured by, for example, immunohistochemistry (IHC-P), reverse transcription polymerase chain reaction(RT-PCR), and immununoblotting. The activation of p53 can also be measured by the induction of apoptosis via the caspase cascade and using methods including, for example, Annexin V staining, TUNEL assays, pro-caspase and caspase levels, and cytochrome c levels. Another consequence of p53 activation is senescence, which can be measured using methods such as galactosidase staining.

[0110] In some embodiments, the method provided herein is in vitro, wherein the method comprises contacting the mutant p53 protein with an effective amount of a compound or a salt thereof descried herein. In some embodiments, the method is in vivo, wherein the method comprises contacting the mutant p53 protein in a subject in need thereof with an effective amount or a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described herein.

[0111] In some embodiments, the method provided herein increases the ability of a p53 mutant to bind to DNA by at least about 0.1%, such as at least about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the ability of the p53 mutant to bind to DNA in the absence of the method. In some embodiments, the method provided herein increases the ability of a p53 mutant to bind to DNA by up to about 0.1%, such as up to about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the ability of the p53 mutant to bind to DNA in the absence of the method. In some embodiments, the p53 mutant comprises a Y220C mutation, with or without other mutations.

[0112] In some embodiments, the method provided herein increases the DNA-binding activity of the Y220C mutant by at least about 2-fold, such as by at least about any of 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, at least or up to about 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, at least or up to about 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, 150-fold, 160-fold, 170-fold, 180-fold, 190-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450- fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800-fold, 850-fold, 900-fold, 950-fold, 1,000-fold, 1,500-fold, 2.000-fold, 3,000-fold, 4,000-fold, 5,000-fold, 6,000-fold, 7,000-fold, 8,000-fold, 9,000-fold, or 10,000-fold compared to the ability of Y220C to bind DNA in the absence of the method. In some embodiments, the method provided herein increases the DNA-binding activity of the Y220C mutant by up to about 2-fold, such as by up to about any of 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, at least or up to about 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, at least or up to about 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, 100-fold, 110-fold, 120-fold, 130- fold, 140-fold, 150-fold, 160-fold, 170-fold, 180-fold, 190-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800- fold, 850-fold, 900-fold, 950-fold, 1,000-fold, 1,500-fold, 2.000-fold, 3,000-fold, 4,000-fold, 5,000-fold, 6,000-fold, 7,000-fold, 8,000-fold, 9,000-fold, or 10,000-fold compared to the ability of Y220C to bind DNA in the absence of the method.

[0113] In some embodiments, the method provided herein increases the stability of a p53 mutant by at least about 0.1%, such as at least about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the stability of the p53 mutant in the absence of the method. In some embodiments, the method provided herein increases the stability of a p53 mutant by up to about 0.1%, such as up to about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the stability of the p53 mutant in the absence of the method. In some embodiments, the p53 mutant comprises a Y220C mutation, with or without other mutations.

[0114] In some embodiments, the method provided herein restores the wild-type function of a p53 mutant by at least about 5%, such as at least about any of 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100%. In some embodiments, the method provided herein restores the wild-type function of a p53 mutant by up to about 5%, such as up to about any of 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100%. In some embodiments, the p53 mutant comprises a Y220C mutation, with or without other mutations. Treating proliferative disorders

[0115] In some embodiments, provided herein is a method of inducing apoptosis, cell cycle arrest, and / or senescence in a cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cell carries a mutation in p53. In some embodiments, the method is in vitro. In some embodiments, the method is in vivo.

[0116] In some embodiments, provided herein is a method of treating a proliferative disorder comprising administering an effective amount or a therapeutically effective amountof a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0117] In some aspects, provided herein is a method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I- 3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0118] In some embodiments, the proliferative disorder is associated with a mutant p53 protein. In some embodiments, also provided herein is a method of preventing a proliferative disorder. In some embodiments, the mutant p53 protein comprises a Y220C mutation, with or without other mutations. In some embodiments, the proliferative disorder is a cancer.

[0119] In some embodiments, provided herein is a method of treating cancer.

[0120] In some embodiments, provided herein is a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0121] In some embodiments, the method is to slow the proliferation of cancer cell lines, or kill cancer cells. In some embodiments, also provided herein is a method of preventing cancer. In some embodiments, the cancer is associated with a p53 protein comprising a Y220C mutation, with or without other mutations.

[0122] In some embodiments, the method of treating a proliferative disorder comprises comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein each of the Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), is as defined herein. In some embodiments, the method of treating cancer comprises comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula (O), Formula (A-I),Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein each of the Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), is as defined herein.

[0123] In some embodiments, the method provided herein slows the progression of cancer in a subject in need thereof by at least about 0.5%, such as at least about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. In some embodiments, the method provided herein slows the progression of cancer in a subject in need thereof by up to about 0.5%, such as up to about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method.

[0124] In some embodiments, the method provided herein reduces the likelihood of development of a proliferative disorder or any symptom thereof in a subject in need thereof by at least about 0.5%, such as at least about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. In some embodiments, the method providedherein reduces the likelihood of development of a proliferative disorder or any symptom thereof in a subject in need thereof by up to about 0.5%, such as up to about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method.

[0125] In some embodiments, the method provided herein delays the development of a proliferative disorder or any symptom thereof in a subject in need thereof by at least about 0.5%, such as at least about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. In some embodiments, the method provided herein delays the development of a proliferative disorder or any symptom thereof in a subject in need thereof by up to about 0.5%, such as up to about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. IV. Composition

[0126] In some aspects, provided herein is a composition comprising a mutant p53 protein and a p53 stabilizer having a covalent bond to the mutant p53 protein, wherein the mutant p53 protein comprises a Y220C mutation, and the covalent bond is formed between a -CN group of the p53 stabilizer and the cysteine at position 220 in the mutant p53 protein. In someembodiments, the mutant p53 protein has greater wild-type function compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments, the mutant p53 protein has a greater wild-type conformation compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments, the stabilizer is selectively binds to the cysteline at position 220 in the mutant p53 protein compared to other positions within the protein (e.g., compared to other cysteines in the protein). In some embodiments, the p53 stabilizer is a compound of Formula (O), Formula (A-I), Formula (A-I-1), Formula (A-I-2), Formula (A-I-3), Formula (A-I-4), Formula (A-II), Formula (A-III), Formula (B), Formula (B-I), and Formula (B-II), Table 1, or Table 2, or Compound X, or a pharmaceutically acceptable salt thereof. V. Formulation

[0127] In some embodiments, the compounds provided herein can be formulated in a formulation, such as a pharmaceutical formulation. In some embodiments, the formulation further comprises one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical formulation includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are formulations, such as pharmaceutical formulations that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the formulation may be sterile or contains components that are sterile. Sterilization can be achieved by methods known in the art. In some embodiments, the formulation comprises one or more compounds that are substantially pure (e.g., with a purity of at least about any of 85%, 90%, 95%, 98%, 99%,99.5%, 99.9%, or 99.99%). In some embodiments, especially wherein a formulation is administered by inhalation, injection, or other parenteral administration including the routes listed herein, or wherein a formulation is used for oral, gastric, gastrointestinal, or enteric administration, the formulations and preparations used in the methods disclosed herein are sterile. Methods for preparing sterile,pharmaceutically acceptable compositions include steam sterilization, dry-heat sterilization, gas sterilization, ionizing radiation, or sterile filtration. Sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards (United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7; 16 California Code of Regulations 1751, 21 Code of Federal Regulations 211) known to those of skill in the art. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0129] Also provided are packaged pharmaceutical formulations, comprising a pharmaceutical formulation as described herein and instructions for using the formulation to treat a patient suffering from a disease or condition described herein. VI. Dose and method of administration

[0130] The compounds and compositions described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state. While human dosage levels have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.01 to 100 mg / kg of body weight; in some embodiments, from about 0.05 to 10.0 mg / kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg / kg of body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day. The amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500mg per day, and an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetics.

[0131] Administration of the compounds and compositions described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0132] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[0133] The compounds disclosed and / or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and / or described herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0134] In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and / or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin,cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in a gelatin capsule.

[0135] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and may be higher if the composition is a solid which will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of a compound disclosed and / or described herein in solution.

[0136] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[0137] In addition, pharmaceutical compositions can include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein. VII. Kits

[0138] Also provided herein are kits for carrying out the methods described herein, which comprises one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmacological composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of a fibrotic disease.

[0139] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf-life permit. One or more components of a kit may be sterile and / or may be contained within sterile packaging.

[0140] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for a disease detailed herein (e.g., fibrosis) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0141] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods described herein. The instructions included with the kit generally include information as to the components and their administration to an individual. ENUMERATED EMBODIMENTS

[0142] The following enumerated embodiments are representative of some aspects of the invention. 1. A compound of Formula (O) , or a salt thereof, wherein:A2is N or CR2; and A3is N or CR3; provided that no more than one of A2and A3is N;X is N or CR5; RNis H, D, C1-C3alkyl optionally substituted with one or more independently selected RN1, or C3-C5cycloalkyl optionally substituted with one or more halo; RN1is halo; or cyclopropyl optionally substituted with one or more independently selected halo, R1and R4are independently selected from the group consisting of H, D, and halo, provided that when X is N at least one of R1and R4is halo; one of R2and R3is -N(Ra)-L1-R2a, -N(Ra)-C(O)-R2b, -N(Ra)-C(O)-N(Ra)-R2c, -N(Ra)-R2d, - N(Ra)-M1-N(Ra)-R2e, -N(Ra)-M2-M3-L2-R2f, -N(Ra)-M4-M5-C(O)-N(Ra)-R2g, -N(Ra)-M6-M7- O-R2h, -C(O)-N(Ra)-(L3)n-R2i, -N(Ra)-M8-N(Ra)-L4-R2j, -N(Ra)-M9-N(Ra)-L5-C(O)-R2k, - N(R2l)-C(O)-N(Ra)-L6-R2m, or -N(Ra)-M10-R2n, R2ais 3- to 14-membered heterocyclyl, 5- to 6-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2bis 3- to 14-membered fully saturated heterocyclyl optionally substituted with one or more independently selected R20; R2cis 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2dis C3-C14cycloalkyl or 3- to 14-membered fully saturated heterocyclyl, each of which is optionally substituted with one or more independently selected R20; R2eis 3- to 14-membered heterocyclyl, C6-C12aryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2f, R2g, R2h, R2i, R2j, R2k, R2l, R2m, and R2n, at each occurrence, are independently 3- to 14- membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; wherein each R20is D, halo; -CN; oxo; -COORa; -N(Ra)2; -ORa; -O-(5- to 12-membered heteroaryl); -SO2Ra; -N(Ra)-C(O)-Ra; -N(Ra)-C(O)-N(Ra)2; -C(O)-N(Ra)2; -C(O)-N(Ra)-R20a; -C(O)-N(Ra)-L7-ORa; C1-C6alkyl optionally substituted with one or more independently selected -ORa, -C(O)ORa, or -SO2Ra; C6-C14aryl optionally substituted with one or moreindependently selected halo or -ORa; 5- to 14-membered heteroaiyl optionally substituted with one or more independently selected halo or C1-C6alkyl; C3-C14cycloalky] optionally substituted with one or more independently selected -ORaor -SO2Ra; 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected halo; or C2-C6alkynyl optionally substituted with one or more independently selected halo or - N(Ra)C(O)ORa; wherein R20ais C3-C8cycloalkyl optionally substituted with one or more halo: -CN; orthe other one of R2and R3, if present, is H, D, halo, -NO2, -COORa, -C(O)-N(Ra)2, -N(R8)- C(O)-Ra. 5- to 14-membered heteroaryl, C1-C6alkyl optionally substituted with one or more independently selected -N(Ra)2or halo, or C3-C6cycloalkyl optionally substituted with one or more independently selected -N(Ra)2or halo;R5, if present, is H, D, halo, C1-C6alkyl optionally substituted with one or more independently selected halo, or C3-C6cycloalkyl optionally substituted with one or more independently selected halo; L1, L2, L3, L4, L5, L6, and. L7. at each occurrence, are independently C1-C6alkylene optionally substituted with one or more independently selected -OH. -CN, halogen, or C3-C6cycloalkyl; n is 0 or 1 ; M1, M2, M3, M4, M5, M6, M7, M8, M9, and M10, at each occurrence, are independently C3-C14cycloalkylene or 3- to 14-membered heterocyclylene, each of which is optionally substituted by one or more substituents independently selected from the group consisting of oxo, -CN, halo, -OH, -OD, C1-C6alkyl, C3-C6cycloalkyl, and -C(O)-N(Ra)?,; and wherein Ra, at each occurrence, is independently II; D; C1-C6alkyl optionally substituted with one or more independently selected halogen. -OH. -OD. -O-(C1-C3alkyl), or oxo; or C3- C6cycloalkyl optionally substituted with one or more independently selected halogen, -OH, - OD, -O-(C1- C3alkyl), or oxo.2. The compound of embodiment 1, or a salt thereof, wherein RNis H or D.3. The compound of embodiment 1, or a salt thereof, wherein RNis C1-C3alkyl optionally substituted with one or more independently selected halo or C3-C6cycloalkyl. 4. The compound of embodiment 3, or a salt thereof, wherein RNis C1-C3alkyl substituted with three F. 5. The compound of embodiment 3 or embodiment 4, or a salt thereof, wherein RNis - CH2CF3. 6. The compound of embodiment 3, or a salt thereof, wherein RNis C1-C3alkyl substituted with cyclopropyl. 7. The compound of embodiment 1, or a salt thereof, wherein RNis C3-C5cycloalkyl optionally substituted with one or more halo. 8. The compound of embodiment 7, or a salt thereof, wherein RNis C3-C5cycloalkyl substituted with one or more F. 9. The compound of any one of embodiments 1-8, or a salt thereof, wherein one of R2and R3is -N(Ra)-L1-R2a, -N(Ra)-R2d, -N(Ra)- M5-N(Ra)-R2e, -N(Ra)-M2-M3-L2-R2f, -N(Ra)- M4-M5-C(O)-N(Ra)-R2g, -N(Ra)-M6-M7-O-R2h, -N(Ra)-M8-N(Ra)-L4-R2j, N(Ra)-M9-N(Ra)-L5- C(O)-R2k, or -N(Ra)-M10-R2n. 10. The compound of any one of embodiments 1-9, or a salt thereof, wherein one of R2and R3is -N(Ra)-L1-R2a, wherein R2ais 3- to 14-membered heterocyclyl, 5- to 6-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20. 11. The compound of any one of embodiments 1-10, or a salt thereof, wherein one of R2and R3is -N(Ra)-L1-R2a, and wherein R2ais 5- to 6-membered heteroaryl or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected halo, -CN, -NH2, -CH2C(O)OCH2CH3, or C1-C6haloalkyl. 12. The compound of any one of embodiments 1-11, or a salt thereof, wherein one of R2and R3is -N(Ra)-L1-R2a, and wherein L1is C1-C3alkylene.13. The compound of any one of embodiments 1-12, or a salt thereof, wherein one of R2and R3is14. The compound of any one of embodiments 1 -9, or a salt thereof, wherein one of R and R3is -N(Ra)-R2d, wherein R2dis C3-C14cycloalkyl or 3- to 14-membered fully saturated heterocyclyl, each of which is optionally' substituted with one or more independently selected R20.15. The compound of any one of embodiments 1-9 and 14, or a salt thereof, wherein one of R2and R3is -N(Ra)-R2d, wherein R2dis 5- to 6-membered fully saturated heterocyclyl optionally substituted with one or more independently selected R20.16. The compound of any one of embodiments 1-9, 14, and 15, or a salt thereof, wherein one of R2and R ' is17. The compound of any one of embodiments 1-9, or a. salt thereof, wherein one of R2and R3is -N(Ra)-R2dwherein R2dis C3-C14cycloalkyd optionally substituted with one or more independently selected R20.18. The compound of any one of embodiments 1 -9 and 17, or a salt thereof, wherein one of R2and R3is -N(Ra)-R2d, wherein R2dis C3-C8cycloalkyl optionally substituted, with one or more independently selected -N(Ra)2. -N(Ra)-C(O)-Ra. or -N(Ra)-C(O)-N(Ra)2. wherein Ra, at each occurrence, is independently H, D, or C1-C6alkyl optionally substituted with one or more independently selected halogen, -OH, -OD, or -O-(C1-C3alkyl).19. The compound of any one of embodiments 1-9, 17, and 18, or a salt thereof, wherein one of R2and R'' is20. The compound of any one of embodiments 1-9, 17, and 18, or a salt thereof, wherein one of R2and R3is21. The compound of any one of embodiments 1 -9, or a salt thereof, wherein one of R2and R3is -N(Ra)-M1-N(Ra)-R2e, and wherein R2eis 3- to 14-membered heterocyclyl, C6-C12aryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20.22. The compound of any one of embodiments 1 -9 and 21 , or a salt thereof, wherein one of R2and R3is -N(Ra)-M1-N(Ra)-R2e, and wherein M1is cyclohexylene.23. The compound, of any one of embodiments 1-9, 21, and 22, or a salt thereof, wherein one of R2and R3is -N(Ra)-M1-N(Ra)-R2c, and wherein R2cis 3- to 14-membered heterocyclyl, C6-C12aryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected, oxo; halo; 5 to 6-membered heterocyclyl; -OH: -OD; -N(Ra)-C(O)-Ra; -C'(O)-N(Ra)2; C1-C6alkyl optionally substituted with one or more -OH or - OD; C6-C14aryl optionally substituted with one or more independently selected -ORa; or 5- to 14-membered heteroaryl optionally substituted with C1-C6alkyl.24. The compound of any one of embodiments 1-9 and 21-23. or a salt thereof, wherein one of R* and R3, is25. The compound of any one of embodiments 1 -9, or a salt thereof, wherein one of R2and R3is -N(Ra)-M2-M3-L2-R2f, wherein R2fis 3- to 14-membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaiyl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20.26. The compound of any one of embodiments 1-9 and 25, or a salt thereof, wherein one of R2and R3is -N(Ra)-M2-M3-L2-R2f, wherein R2:is 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R20.27. The compound of any one of embodiments 1-9, 25, and 26, or a salt thereof, wherein one of R2and R3is -N(Ra)-M2-M3-L2-R2f, wherein M2is cyclohexylene.28. The compound, of any one of embodiments 1-9 and 25-27, or a salt thereof, wherein one of R2and R3is -N(Ra)-M2-M3-L2-R2f, wherein M3is 5- to 6-membered heterocyclylene.29. The compound of any one of embodiments 1-9 and 25-28, or a. salt thereof, wherein one of R2and R2is -N(Ra)-M2-M3-L2-R2f, wherein 1,2 is C1-C3alkylene.30. The compound of any one of embodiments 1-9 and 25-29, or a salt thereof, wherein one of R2and R° is31. The compound of any one of embodiments 1 -9, or a salt thereof, wherein one of R2and R.3is -N(Ra)-M4-M5-C(O)-N(Ra)-R2g, wherein M4is cyclohexylene.32. The compound, of any one of embodiments 1-9 and 31, or a salt thereof, wherein one of R2and R3is -N(Ra)-M4-M5-C(O)-N(Ra)-R28, wherein M5is 5- to 8-membered heterocyclylene.33. ’The compound of any one of embodiments 1-9, 31 , and 32, or a salt thereof, wherein one of R2and R2' is -N(Ra)-M4-M5-C(O)-N(Ra)-R2g, wherein R2gis 3- to 14-membered heterocyciyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20.34. The compound of any one of embodiments 1 -9 and 31 -33, or a salt thereof, wherein one of R2and R3is -N(Ra)-M4-M5-C(O)-N(Ra)-R2g, wherein R2gis 3- to 14-membered heterocyciyl or C3-C8cycloalkyl, each of which is optionally substituted with one or more independently selected R20.35. The compound of any one of embodiments 1-9 and 31-34, or a salt thereof, wherein one of R2and R3is36. Tire compound of any one of embodiments 1-9, or a salt thereof, wherein one of R2and R3is -N(Ra)-M6-M7-O-R2h, wherein Me is cyclohexylene..37. ’The compound of any one of embodiments 1-9 and 36, or a salt thereof, wherein one of R2and R2is -N(Ra)-M6-M7-O-R2n, wherein M7is 4- to 6-membered heterocyclylene.38. The compound of any one of embodiments 1-9, 36, and 37, or a salt thereof, wherein one of R2and R3is -N(Ra)-M6-M7-O-R2“, wherein R2his 3- to 14-membered heterocyciyl, C6-Ciz aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalky l, each of which is optionally substituted with one or more independently selected R20.39. The compound of any one of embodiments 1-9 and 36-38. or a. salt thereof, wherein one of R2and R3is -N(Ra)-M6-M7-O-R2h, wherein R2his C6-C12aryl or 5- to 14-membered heteroaryl, each of which is optionally substituted with one or more independently selected R20.40. The compound of any one of embodiments 1-9 and 36-39, or a salt thereof, wherein one of R2and R3is41. The compound of any one of embodiments 1-9, or a. salt thereof, wherein one of R2and R3is -N(Ra)-M8-N(Ra)-L4-R2j, wherein M8is C3-C8cycloalkylene.42. The compound of any one of embodiments 1-9 and 41, or a salt thereof, wherein one of R2and R5is -N(Ra)-M8-N(Ra)-L4-R2j, wherein L4is C1-C3alky lene.43. The compound of any one of embodiments 1 -9, 41, and 42. or a stilt thereof wherein one of R2and R3is -N(Ra)-M8-N(Ra)-L4-R2j, wherein R2jis 3- to 14-membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20.44. Hie compound of any one of embodiments 1-9 and 41-43. or a. salt thereof, wherein one of R2and R3is -N(Ra)-M8-N(Ra)-L4-R2j, wherein R2Jis C6-C12aryl or 5- to 14-membered heteroary l, each of which is optionally substituted with one or more independently selected R2G.45. The compound of any one of embodiments 1-9 and 41-44, or a salt thereof, wherein one of R2and R3is46. Tlie compound of any one of embodiments 1-9 and 41-44, or a salt thereof, wherein one of R2and R3is47. The compound of any one of embodiments 1-9, or a salt thereof, wherein one of R2and R3is N(Ra)-M9-N(Ra)-L5-C(O)-R2k, wherein Mg is cyclohexylene.48. Tlie compound of any one of embodiments 1-9 and 47, or a salt thereof, wherein one of R2and Rdis N(R3)-M9-N(Ra)-L5-C(O)-R2k, wherein L5is C1-C6alkylene.49. The compound of any one of embodiments 1-9, 47, and 48, or a salt thereof, wherein one of R2and R3is N(Ra)-M9-N(Ra)-L5-C(O)-R2k, wherein R2kis 3- to 14-membered heterocyclyl, C6-C12aryl, 5- to 14-membered heteroaryl, or C3-Cn cycloalkyl, each of which is optionally substituted with one or more independently selected R20.50. Tlie compound of any one of embodiments 1-9 and 47-49, or a salt thereof, wherein one of R2and R3is N(Ra)-M9-N(Ra)-L5-C(O)-R2k, wherein R2kis 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected R20.51. The compound of any one of embodiments 1-9 and 47-50. or a salt thereof, wherein one of R2and R3is52. The compound of any one of embodiments 1 -9, or a salt thereof, wherein one of R2and R3is -N(Ra)-M10-R2n, wherein M10is cyclohexylene.53. The compound of any one of embodiments 1-9 and 52, or a salt thereof, wherein one of R2and R3is -N(Ra)-M10-R2n, wherein R2nis 3- to 14-membered heterocyclyl, C6-C12and.5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20.54. The compound of any one of embodiments 1-9, 52, and 53, or a salt thereof, wherein one of R2and R3is -N(Ra)-M10-R2n, wherein R2nis 3- to 14-membered heterocyclyl or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20.55. The compound of any one of embodiments 1-9 and 52-54, or a salt thereof, wherein one of R2and R3is ,, ,56. The compound of any one of embodiments 1-9 and 51-54, or a salt thereof, wherein one of R2and R3is57. The compound of any one of embodiments 1 -9, or a salt thereof, wherein one of R2and R3is -N(Ra)-C(O)-R2b-N(Ra.)-C(O)-N(Ra)-R2c, -C(O)-N(Ra)-(L3)n-R2i, or -N(R2i)-C(O)- N(Ra)-L6-R2m.58. The compound of any one of embodiments 1-9 and 57, or a salt thereof, wherein one of R2and R3is -N(Ra)-C(O)-R2b, and wherein R2bis fully saturated 3- to 8-membered, heterocyclyl optionally substituted with one or more independently selected R20.59. The compound of any one of embodiments 1-9 and 57, or a salt thereof, wherein one of R2and R3is -N(Ra)-C(O)-N(Ra)-R2c, wherein R2cis 3- to 8-membered heterocyclyl optionally substituted with one or more independently selected R20.60. The compound of any one of embodiments 1-9 and 57, or a salt thereof, wherein one of R2and R3is -C(O)-N(R3)-R2ior -C(O)-N(Ra)-L3-R2i, wherein R21is 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected R20.61 . The compound of any one of embodiments 1-9 and 57, or a salt thereof, wherein one of R2and R3is -N(R2l)-C(O)-N(Ra)-L6-R2m, wherein R2lis 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected R20and R2mis C6-C12and optionally substituted with one or more independently selected R20.62. The compound of any one of embodiments 1-9, 57, and 61, or a salt thereof, wherein. one of R2and R3is63. The compound of any one of embodiments 1-62, or a salt thereof, wherein the other one of R2and R3, if present, is H, D. halo, -NO2. -COORa, -C(O)-N(Ra)2. -N(Ra)-C(O)-Ra, 5- to 14-membered heteroaryl, or C1-C6alkyl optionally substituted with one or more independently selected -N(Ra)2.64. The compound of any one of embodiments 1-63, or a salt thereof, wherein the other one of R2and R3, if present, is II or D.65. The compound of any one of embodiments 1-64, or a salt thereof, wherein R1is H. D, or halo.66. The compound of any one of embodiments 1-65, or a salt thereof, wherein R1is H orD67. The compound of any one of embodiments 1-65, or a salt thereof, wherein R1is halo.68. The compound of any one of embodiments 1-65 and 67. or a salt thereof, wherein R1is Br.69. The compound of any one of embodiments 1-68, or a salt thereof, wherein R4is H, D, or halo.70. The compound of any one of embodiments 1-69, or a salt thereof, wherein R4is H or D. 71. The compound of any one of embodiments 1-69, or a salt thereof, wherein R4is Br. 72. The compound of any one of embodiments 1-69, or a salt thereof, wherein R4is Cl. 73. The compound of any one of embodiments 1-72, or a salt thereof, wherein R5, if present, is H, D, halo, or C1-C6alkyl optionally substituted with one or more independently selected halo. 74. The compound of any one of embodiments 1-73, or a salt thereof, wherein R5, if present, is H or D. 75. The compound of any one of embodiments 1-73, or a salt thereof, wherein R5, if present, is H. 76. The compound of any one of embodiments 1-73, or a salt thereof, wherein R5, if present, is F. 77. The compound of any one of embodiments 1-73, or a salt thereof, wherein R5, if present, is CF3. 78. The compound of any one of embodiments 1-77, or a salt thereof, wherein A1is CR1. 79. The compound of any one of embodiments 1-78, or a salt thereof, wherein A2is N. 80. The compound of any one of embodiments 1-78, or a salt thereof, wherein A2is CR2. 81. The compound of any one of embodiments 1-80, or a salt thereof, wherein A3is N. 82. The compound of any one of embodiments 1-80, or a salt thereof, wherein A3is CR3. 83. The compound of any one of embodiments 1-82, or a salt thereof, wherein A4is CR4. 84. The compound of any one of embodiments 1-83, or a salt thereof, wherein X is N. 85. The compound of embodiment 84, or a salt thereof, wherein X is N and one of R1and R4is halo 86. The compound of any one of embodiments 1-84, or a salt thereof, wherein X is CR5. 87. The compound of any one of embodiments 1-78, 80, 82, 83, and 84, or a salt thereof, wherein the compound is of Formula (A-I) I), or a salt thereof.88. Tlie compound of embodiment 1, or a salt thereof, wherein the compound is of Formula (B)or a salt thereof.89. A compound, or a salt thereof, selected from the compounds in Table 1 and Table 2, or a salt thereof.90. A pharmaceutical composition comprising a compound of any one of embodiments 1- 89, or a pharmaceutically acceptable salt thereof, and a. pharmaceutically acceptable carrier or excipient.91. The composition of embodiment 90, wherein the composition is sterile.92. A method of modulating the conformation of a. mutant p53 protein, comprising contacting the mutant p53 protein with air effective amount of the compound of any one of embodiments 1-89. or the composition of embodiment 90 or 91.93. A method of restoring wild-type function of a mutant p53 protein, comprising contacting the mutant p.53 protein with an effective amount of the compound of any one of embodiments 1-89, or a salt thereof, or the composition of embodiment 90 or 91.94. A method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-89. or a salt thereof, or the composition of embodiment 90 or 91.95. Tlie method of embodiment 94, wherein the proliferative disorder is associated with a mutant p53 protein.96. Hie method of embodiment 95, wherein the mutan t p53 protein comprises a Y220C mutation.97. The method of any one of embodiments 94-96, wherein the proliferative disorder is cancer.GENERAL SYNTHETIC EXAMPLES

[0143] The chemical reactions in the Synthetic Examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non -exempli tied compounds according io the invention can be successfully performed by modifications apparent to those skilled in the art. e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art. will be recognized as having applicability for preparing other compounds of the invention.

[0144] Compounds provided herein may be prepared according to Schemes, as exemplified herein. Minor variations in temperatures, concentrations, reaction times, and other parameters can be made when following the Examples and Methods, which do not substantially affect the results of the procedures.METHOD 1 (Ml)

[0145] Int-l converted into title nitrile via. reductive alkylation of amine Ml-1 (obtained commercially or synthesized according to methods known in the art) in the presence of reducing agents such as sodium triacetoxy borohydride. Compounds were purified by prep- HPLC; cis and trans isomers of cyclohexyl diamine were isolated separately, relative stereochemistry of centers on cyclohexyl ring was assigned based on1H NMR.METHOD 2 (M2)

[0146] Int-2 reacted with amine M2-1 (obtained commercially or synthesized according to methods known in the art) under amide coupling conditions to afford title compound. Final compounds were purified by prep-HPLC; cis and trans isomers of cyclohexyl diamine were isolated separately, relative stereochemistry of centers on cyclohexyl ring was assigned based on1H NMR.METHOD 3 (M3)H

[0147] Int-3 reacted with aldehyde M3-1 (obtained commercially or synthesized according to methods known in the art) followed by formaldehyde under reductive amination conditions to afford the final compound.

[0148] For other set of analogs Int~3 reacted with acetyl chloride under basic conditions to afford the title nitrile compound.METHOD 4 (M4)

[0149] Int-4 reacted with acyl chloride M4-1 under basic conditions to afford final product.

[0150] For other set of analogs Int~4 reacted with aldehyde M4-2 tinder reductive amination conditions to afford the title diamine.METHOD 5 (MS)

[0151] Int-S converted into title nitrile via reductive amination of carbonyl compound M5-1 (obtained commercially or synthesized according to methods known in the art) in the presence of reducing agents such as sodium triacetoxyborohydride. Compounds were purified by prep-HPLC.METHOD 6 (M6)

[0152] Compound M6-1 was coupled with secondary or Boc-protected amine M6-2(obtained commercially or synthesized according to methods known in the art) wider Pd- catalyzed or SxAr conditions. Nitro group in compound M6-3 was reduced and diamine M6-4 was subjected to cyclization via 4.5-dichloro-L2,3~dithiazol-2-ylium chloride in pyridine.Intermediate M6-5 was brominated or iodinated by treatment with NBS or iodine yielding title nitrile. In case of Boc-protected amines additional step of HCl or TFA mediated deprotection was performed, to provide final product.EXAMPLESynthetic ExamplesAbbreviations:DIAL) - Diisopropyl azodicarboxylateACN – acetonitrile TFAA – trifluoroacetic anhydride TFA – trifluoroacetic acid BINAP - Bis(diphenylphosphino)-1,1'-binaphthyl DBU - 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM – dichloromethane NBS - N-Bromosuccinimide THF – tetrahydrofuran DPPF - 1,1′-Bis(diphenylphosphino)ferrocene DMSO – dimethyl sulfoxide HATU - Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium DMF – dimethylformamide DIEA - N,N-diisopropylethylamine TCFH - Chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate NMI - N-methylimidazole TEA – triethylamine MOMBr – bromomethylmethylether LDA - Lithium diisopropylamide MTBE, MtBE - tert-Butyl methyl ether PE– petroleum ether EtOAc –ethyl acetate NIS –N-Iodosuccinimide FA – formic acid STAB – sodium triacetoxyborohydride DCE - dichloroethaneDAST - Diethylaminosulfur trifluoride NMP - N-Methyl-2-pyrrolidone DMAP - N N-dimethyl-4-pyridylamine DMA - N,N-Dimethylacetamide BBBPY - 4,4′-Di-tert-butyl-2,2′-dipyridyl TBAF - Tetrabutylammonium fluoride LCMS – Liquid chromatography mass spectrometry Example 1. Preparation of Key Intermediates INTERMEDIATE 1 AND 2Step 1: 2-chloro-5-nitro-N-(2,2,2-trifluoroethyl)pyridin-4-amine

[0153] A solution of compound I1-1 (400 g, 2.07 mol, 1.00 eq), compound I1-2 (307 g, 3.11 mol, 244 mL, 1.50 eq) and TEA (629 g, 6.22 mol, 865 mL, 3.00 eq) in THF (2.00 L) was stirred at 40 °C for 12 h. The mixture was poured into H2O (2.50 L), extracted with EtOAc (1.00 L * 2). The combined organic layers were washed with brine (3.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : EtOAc = 10:1 to 1:1) to give compound I1- 3 (1.30 kg, 5.09 mol, 81.8% yield) as a light yellow solid. LCMS (ES, m / z): 256.0 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.71 (s, 1H), 7.45 (s, 1H), 4.45-4.43 (m, 2H), 0.94-0.90 (m, 3H). Step 2: 5-nitro-N2-(1,4-dioxaspiro[4.5]decan-8-yl)-N4-(2,2,2-trifluoroethyl)pyridine-2,4- diamine

[0154] The solution of compound I1-3 (425 g, 1.66 mol, 1.00 eq), compound I1-4 (365 g, 2.33 mol, 1.40 eq) and TEA (504 g, 4.99 mol, 694 mL, 3.00 eq) in DMF (2.00 L) was stirred at 90 °C for 12 h. The mixture was poured into H2O (15.0 L), extracted with EtOAc (2.00 L * 2). The organic layer was washed with brine (5.00 L * 2), dried over Na2SO4, concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: EtOAc = 20:1 to 1:1). Compound I1-5 (1.82 kg, 4.84 mol, 72.7% yield) was obtained as a light-yellow solid. LCMS (ES, m / z): 377.3 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.30 (brs, 1H), 7.59 (d, J = 8 Hz, 1H), 5.85 (s, 1H), 4.19 (brs, 1H), 3.89-3.83 (m, 4H), 1.84-1.80 (m, 2H), 1.72-1.69 (m, 3H), 1.58-1.48 (m, 3H). Step 3: N2-(1,4-dioxaspiro[4.5]decan-8-yl)-N4-(2,2,2-trifluoroethyl)pyridine-2,4,5-triamine

[0155] The solution of compound I1-5 (200 g, 531 mmol, 1.00 eq) and Pd / C (20.0 g, 18.7 mmol, 10% purity) in MeOH (1.00 L) was stirred at 25 °C for 12 h under H2(50 psi). The mixture was filtered through celite, and the filtrate was concentrated under vacuum to yield crude product which was used in next step without further purification. Compound I1-6 (900 g, 2.42 mol, 91.1% yield, 93.2% purity) was obtained as a violet solid. LCMS (ES, m / z): 347.1 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 1H), 5.77 (s, 1H), 5.71 - 5.68 (m, 1H), 5.26 (d, J = 8 Hz, 1H), 3.88 – 3.86 (m, 2H), 3.84-3.82 (m, 4H), 3.68 (s, 2H), 3.61-3.51 (m, 1H), 1.81-1.79 (m, 2H), 1.69-1.66 (m, 2H), 1.51-1.48 (m, 2H), 1.41-1.38 (m, 2H). Step 4: (E)-5-((4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino)-N2-(1,4- dioxaspiro[4.5]decan-8-yl)-N4-(2,2,2-trifluoroethyl)pyridine-2,4-diamine HCl salt

[0156] The solution of compound I1-6 (250 g, 721 mmol, 1.00 eq) and compound I1-7 (331 g, 1.59 mol, 2.20 eq) in DCM (2.50 L) was stirred at 25 °C for 1 hr. The mixture wasconcentrated under vacuum. The crude product was triturated with petroleum ether : EtOAc = 1:1 (3.00 L) at 25 ºC for 30 mins. Compound I1-8 (1.56 kg, crude) was obtained as a green solid. LCMS (ES, m / z): 482.0 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.84 – 7.80 (m, 1H), 7.19 – 7.09 (m, 1H), 6.35 (s, 1H), 4.43- 4.03 (m, 4H), 3.87 – 3.79 (m, 1H), 1.98 – 1.86 (m, 2H), 1.71 – 1.60 (m, 2H), 1.59 – 1.53 (m, 4H). Step 5: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridine-2-carbonitrile

[0157] A solution of compound I1-8 (300.00 g, 622 mmol, 1.00 eq, QNMR:40%) in pyridine (3.00 L) was heated to 100 °C and stirred at 100 °C for 1 hr. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (DCM (0.1%TEA): EtOAc = 1: 0 to 1: 1, petroleum ether: EtOAc = 1: 1). Compound I1-9 (119 g, 280 mmol, 41.8% yield, 90% purity) was obtained as a brown solid. LCMS (ES, m / z): 382.3 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 0.8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 5.39 - 5.33(m, 2H), 3.88 - 3.86 (m, 4H), 3.68 (s, 1H), 1.91 - 1.86 (m, 2H), 1.74 - 1.71 (m, 2H), 1.59 - 1.55 (m, 4H). Step 6: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-7-bromo-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile

[0158] To a solution of compound I1-9 (65.0 g, 121 mmol, 71% purity, 1.00 eq) in MeCN (600 mL) was added NBS (30.1 g, 169 mmol, 1.40 eq). The mixture was stirred at 25 °C for 1 hr. The mixture was poured into H2O (2.00 L), extracted with DCM (800 mL * 2). The combined organic layers were washed Na2O3S2solution 800 mL * 2), dried over Na2SO4, filtered, and concentrated to give the crude product. It was used next step without further purification. Compound I1-10 (135 g, crude) was obtained as a yellow oil. LCMS (ES, m / z): 462.1 [M-H]-. Step 7: 7-bromo-6-((4-oxocyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridine-2-carbonitrile

[0159] The solution of compound I1-10 (130 g, 282 mmol, 1.00 eq) in TFA (2.00 kg, 17.5 mol, 1.30 L, 61.9 eq) was stirred at 25 °C for 12 h. The mixture was concentrated to remove most of TFA. Then the mixture was adjusted to pH = 8 with Na2CO3solution and extracted with DCM (800 mL * 2). The combined organic layers were washed with brine (1.50 L), dried over Na2SO4, concentrated. The residue was purified by column chromatography (SiO2, silica gel chromatography (DCM (0.1%TEA): EtOAc = 1: 0 to (DCM (0.1%TEA): EtOAc = 1: 1)) to give crude product. Then the crude product was triturated with MTBE (300 mL) at25 ºC for 16 h. Int-1 (30.1 g, 70.3 mmol, 24.8% yield, 97.2% purity) was obtained as an orange solid. LCMS (ES, m / z): 418.1 [M-H]+.1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 6.28 (d, J = 7.6 Hz, 1H), 5.60 - 5.53 (m, 2H), 4.56 – 4.48 (m, 1H), 2.56 - 2.55 (m, 2H), 2.26- 2.22 (m, 2H), 2.16 – 2.14 (m, 2H), 2.12 – 1.86 (m, 2H). Step 8: 7-(4-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid

[0160] A solution of Int-1 (10 g, 24.027 mmol, 1 eq), I1-11 (5.12 g, 28.832 mmol, 1.2 eq), TEA (3.65 g, 36.041 mmol, 1.5 eq), STAB (12.22 g, 57.665 mmol, 2.4 eq) in DMF (5 mL) and DCM (85 mL) was stirred for 10 minutes at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 6 hours at 50°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NaHCO3(aq.) (5 mL) at room temperature. The mixture was acidified to pH 4 with citric acid. The resulting mixture was extracted with EtOAc (3 x 350 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column eluting with H2O (0.1%FA) / MeCN (0.1%FA) (1 / 4) to afford Int-2 (7.3 g, 55.00%) as a yellow solid. LC-MS (ES, m / z): 541.15, 543.15 [M+H]+. INTERMEDIATE 3Step 1: N-[4-({5-nitro-4-[(2,2,2-trifluoroethyl)amino]pyridin-2- yl}amino)bicyclo[2.2.2]octan-1-yl]carbamate

[0161] A mixture of I3-1 (1 g, 3.333 mmol, 1 eq) and I3-2 (0.96 g, 4.000 mmol, 1.2 eq) and Pd PEPPSI-IPentCl (0.29 g, 0.333 mmol, 0.1 eq) and Cs2CO3(3.26 g, 9.999 mmol, 3 eq) in dioxane (10 mL) was stirred for overnight at 100°C under nitrogen atmosphere. Theresulting mixture was added H2O (50 mL) and extracted with EtOAc (3 x50 mL). The combined organic layers were washed with H2O (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (2:1) to afford I3- 3 (1.1 g, 71.83%) as a yellow solid. LC-MS (ES, m / z): 460.47 [M+H]+. Step 2: tert-butyl N-[4-({5-amino-4-[(2,2,2-trifluoroethyl)amino]pyridin-2- yl}amino)bicyclo[2.2.2]octan-1-yl]carbamate

[0162] A mixture of I3-3 (1.1 g, 2.394 mmol, 1 eq) and B2(OH)4 (0.86 g, 9.576 mmol, 4.00 eq) and4,4'-dimethoxy-2,2'-bipyridine (0.05 g, 0.231 mmol, 0.10 eq) in DMF (11 mL) was stirred for10 min at room temperature. The resulting mixture was added H2O (50 mL) and extracted with EtOAc (3 x50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (5:1) to afford I3-4 (500 mg, 48.63%) as a red solid. LC-MS (ES, m / z): 430.48 [M+H]+. Step 3: 4-{[6-({4-[(tert-butoxycarbonyl)amino]bicyclo[2.2.2]octan-1-yl}amino)-4-[(2,2,2- trifluoroethyl)amino]pyridin-3-yl]amino}-5-chloro-1lambda4,2,3-dithiazol-1-ylium

[0163] A mixture of I3-4 (500mg, 0.303 mmol, 1 eq) and I3-5 (78.57 mg, 0.455 mmol, 1.5 eq) in DCM (2 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (2:1) to afford I3-6 (300 mg, 58.36%) as a yellow oil. LC-MS (ES, m / z): 565.08[M+H]+. Step 4: 6-({4-aminobicyclo[2.2.2]octan-1-yl}amino)-1-(2,2,2-trifluoroethyl)imidazo[4,5- c]pyridine-2-carbonitrile

[0164] A mixture of I3-6 (300 mg, 0.177 mmol, 1 eq) and HCl(gas)in 1,4-dioxane (0.6 mL, 4M) in DMF (3mL) was stirred for overnight at 80°C. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% FA), 0% to 30% gradient in 20 min to afford I3-7 (65 mg, 31.69%) as a white solid. LC-MS (ES, m / z):365.37 [M+H]+. Step 5: 6-({4-aminobicyclo[2.2.2]octan-1-yl}amino)-7-bromo-1-(2,2,2- trifluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile

[0165] A mixture of I3-7 (50 mg, 0.137mmol) and NBS (24mg, 0.137 mmol) in MeCN (1 mL) was stirred for0.5 h at room temperature. The resulting mixture was quenched with H2O (10 mL) and extracted with EtOAc (3 x20 mL). The combined organic layers were washed with H2O (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford Int-3 (96 mg) as a white solid. LC-MS (ES, m / z):443.27.445.27 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.24 (s, 3H), 5.55 (q, J = 8.6 Hz, 2H), 5.45 – 5.35 (m, 1H), 2.20 – 2.10 (m, 6H), 1.92 – 1.81 (m, 6H). INTERMEDIATE 4Step 1: tert-butyl ((1r,4r)-4-((5-nitro-4-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)amino)cyclohexyl)carbamate

[0166] A solution of I4-1 (10 g, 33.329 mmol, 1 eq), DIEA (15.1 g, 116.831 mmol, 3.51 eq) and I4-2 (10.0 g, 46.662 mmol, 1.40 eq) in NMP (20 mL) was stirred for 2 days at 110°C.The reaction was quenched with H2O at room temperature. The product was precipitated by the addition of H2O. The precipitated solids were collected by filtration and washed with H2O (2x10 mL). The resulting solid was dried under infrared light to afford I4-3 (11 g, 76.15%) as a yellow solid. LCMS (ES, m / z):434.19 [M+H]+. Step 2: tert-butyl ((1r,4r)-4-((5-amino-4-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)amino)cyclohexyl)carbamate

[0167] A solution of I4-3 (11 g, 25.379 mmol, 1 eq) and Pd / C (5.51 g, 51.773 mmol, 2.04 eq) in EtOAc (150 mL) was stirred for overnight at room temperature under hydrogen atmosphere. The precipitated solids were collected by filtration and washed with EtOAc (2x20 mL). The filtration was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford I4-4 (9.5 g, 92.78%) as a purple solid. LCMS (ES, m / z):404.22 [M+H]+.Step 3: tert-butyl ((1r,4r)-4-((5-(((E)-4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino)-4- ((2,2,2-trifluoroethyl)amino)pyridin-2-yl)amino)cyclohexyl)carbamate

[0168] A solution of I4-4 (2 g, 4.957 mmol, 1 eq), pyridine (1.3 g, 16.435 mmol, 3.32 eq) and I4-5 (1.4 g, 6.715 mmol, 1.35 eq) in DMF (1 mL) was stirred for 4 hours at room temperature. The resulting mixture was concentrated under reduced pressure to afford I4-6 (3 g, 99.56%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ES, m / z):539.12 [M+H]+. Step 4: tert-butyl ((1r,4r)-4-((2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)carbamate

[0169] A solution of I4-6 (3 g, 7.436 mmol, 1 eq) and pyridine (0.9 g, 11.378 mmol, 2.04 eq) in DMF (10 mL) was stirred for 4 hours at 80 °C. The reaction was quenched with H2O at room temperature. The precipitated solids were collected by filtration and washed with H2O (2x5 mL) to afford I4-7 (600 mg, 14.37%) as a black solid. LCMS (ES, m / z):439.20 [M+H]+. Step 5: tert-butyl ((1r,4r)-4-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridin-6-yl)amino)cyclohexyl)carbamate

[0170] A solution of I4-7 (580 mg, 1.217 mmol, 1 eq) and NBS (67.8 mg, 0.857 mmol, 0.66 eq) in MeCN (5 mL) was stirred for 0.5 hour at 0°C.The reaction was quenched with sat. Na2SO3(aq.) at room temperature. The resulting mixture was extracted with EtOAc (2 x10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford I4-8 (450 mg, 63.97%) as a yellow solid. LCMS (ES, m / z):517.11, 519.11 [M+H]+. Step 6: 6-(((1r,4r)-4-aminocyclohexyl)amino)-7-bromo-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile, hydrochloric acid

[0171] A mixture of I4-8 (200 mg, 0.387 mmol, 1 eq) in HCl in 1,4-dioxane (5 mL) was stirred for 0.5 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl ether (10 mL) to afford Int-4 (51.4 mg, 28.98%) as a yellow solid. LCMS: (ES, m / z): 417.20, 419.20 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.08-7.95 (m, 3H), 6.16 (d, J = 7.9 Hz, 1H), 5.57-5.53 (m, 2H), 4.12-3.97 (m, 1H), 2.97-2.89 (m, 1H), 2.04-1.93 (m, 4H), 1.55-1.43 (m, 4H).INTERMEDIATE 5

[0172] A solution of 2-bromo-5-nitro-N-(2,2,2-trifJuoroethyl)pyridin-4-amine (16 g, 53.327 mmol, 1 eq) and bis[(4-methoxyphenyl)methyl]amine (20.86 g, 81.057 mmol, 1.52 eq) in DMSO (160 mL) was stirred for ih at 80°C under air atmosphere. The resulting mixture was diluted with EtOAc (3 x 10mL). Hie combined organic layers were washed with H2O (3x10 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford title compound 15-2(12 g, 42.51%) as a brown oil. LCMS (ES, m / z); 477.20 [ M + H | .

[0173] A solution of 15-2 (10 g, 20.988 mmol, 1 eq) and Fe (2.00 g. 35.889 mmol. 1 .71 eq) NH4CI (3.00 g, 56.038 mmol, 2.67 eq) m EtOH (39 mL) H2O (13 mL, 5.457 mmol) was stirred for 1 hour at 80°C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 10ml..). The combined organic layers were washed with H2O (3x10 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford crude title compound 15-3 (12 g) as a brown oil, LCMS (ES, m z): 447.20 [M+H]+.

[0174] A solution of 15-3 (7 g, 15.678 mmol, 1 eq) and 4,5-dichloro-5H-l,2,3-ditbiazole (4.20 g, 24.144 mmol, 1 .54 eq) in DCM (70 mL) was stirred for 1 hour at room temperature under air atmosphere. The resulting mixture was extracted with EtOAc (3 x lOmL). The combined organic layers were washed with H2O (3x10 mL). dried over anhydrous Na2SCL.After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (5:1) to afford title compound I5-4 (3.5 g, 34.52%) as a yellow solid. LCMS (ES, m / z): 581.10[M+H]+. Step 4: 6-(bis(4-methoxybenzyl)amino)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine- 2-carbonitrile

[0175] A solution of I5-4 (3 g, 5.154 mmol, 1 eq) in pyridine (30 mL) was stirred for 12 hours at 60°C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with H2O (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (5:1) to afford title compound I5-5 (2 g, 72.53%) as a yellow solid. LCMS (ES, m / z): 482.20 [M+H]+. Step 5: 6-amino-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile

[0176] A solution of I5-5 (3 g, 6.231 mmol, 1 eq) in TFA (30 mL) was stirred for 1 hour at room temperature under air atmosphere. The crude product I5-6 was used in the next step directly without further purification. LCMS (ES, m / z): 242.10 [M+H]+. Step 6.6-amino-7-bromo-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile

[0177] A solution of I5-6 (1.4 g, 5.805 mmol, 1 eq) and NBS (1.03 g, 5.805 mmol, 1 eq) in MeCN (14 mL) was stirred for 1 hour at 0°C under air atmosphere. The reaction was quenched with sat. Na2SO3(aq.) at room temperature. The solution was concentrated, and the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min to afford Int-5 (976.5 mg, 52.35%) as a yellow solid. LCMS (ES, m / z): 319.85, 321.85 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 6.67 (s, 2H), 5.54 (q, J = 8.6 Hz, 2H). Example 2. Preparation of 5-Azabenzimidazoles with amino substitution at position 6 METHOD 1 (M1)

[0178] Int-1 converted into title nitrile via reductive alkylation of amine M1-1 (obtained commercially or synthesized according to methods known in the art) in the presence of reducing agents such as sodium triacetoxyborohydride. Compounds were purified by prep- HPLC; cis and trans isomers of cyclohexyl diamine were isolated separately, relative stereochemistry of centers on cyclohexyl ring was assigned based on1H NMR. Examples Compound 1-55 Compound 1-56Step 1: 7-bromo-6-(((1R,4r)-4-((1R,3S,5S)-3-fluoro-8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile and 7-bromo-6-(((1S,4s)-4-((1R,3S,5S)-3-fluoro-8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile

[0179] A solution of Int-1 (20 mg, 0.048 mmol, 1 eq), (1R,3R,5S)-3-fluoro-8- azabicyclo[3.2.1]octane (12 mg, 0.093 mmol, 1.93 eq), STAB (31 mg, 0.146 mmol, 3.04 eq), TEA (24 mg, 0.237 mmol, 4.94 eq) in DCM (1 mL) was stirred for 8 hours at room temperature under nitrogen atmosphere. The reaction was quenched with saturated NaHCO3aqueous at room temperature. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: H2O (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 17% to 42% B in 9 min. The cyclohexyl diamine ring configuration was assigned based on1H NMR.

[0180] 7-bromo-6-(((1R,4r)-4-((1R,3S,5S)-3-fluoro-8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile (3.1 mg, 12.08%) as an off-white solid. LCMS: (ES, m / z): 529.15, 531.15[M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 6.00 (d, J = 7.8 Hz, 1H), 5.54 (q, J = 8.6 Hz, 2H), 5.01– 4.64 (m, 1H), 4.06-3.82 (m, 1H), 3.55-3.45 (m, 2H), 2.03-1.88 (m, 4H), 1.78-1.59(m, 7H), 1.53 – 1.39 (m, 4H), 1.23-1.03 (m, 2H).

[0181] 7-bromo-6-(((1S,4s)-4-((1R,3S,5S)-3-fluoro-8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile (3.8 mg, 14.92%)as a white solid. LCMS: (ES, m / z): 529.15,531.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 5.88 (d, J = 7.4 Hz, 1H), 5.55 (q, J = 8.6 Hz, 2H), 4.98- 4.67(m,1H),4.18-3.98 (m, 1H), 3.54-3.40 (m, 2H), 1.93 – 1.70 (m, 8H), 1.69-1.56(m, 7H), 1.55-1.40 (m, 2H). Compound 1-185 Compound 1-186Step 1: 7-bromo-6-{[(1r,4r)-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl]amino}-1-(2,2,2- trifluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile and 7-bromo-6-{[(1s,4s)-4-[(2- methoxyethyl)(methyl)amino]cyclohexyl]amino}-1-(2,2,2-trifluoroethyl)imidazo[4,5- c]pyridine-2-carbonitrile

[0182] To a stirred solution of Int-1 (80 mg, 0.192 mmol, 1 eq) and 2-methoxyethan-1- amine (21.66 mg, 0.288 mmol, 1.5 eq) and TEA (58.35 mg, 0.576 mmol, 3 eq) in DCE (6 mL) was added STAB (122.21 mg, 0.576 mmol, 3 eq) in portions at room temperature. The resulting mixture was stirred for 2 hours at room temperature. To the above mixture was added HCHO (8.66 mg, 0.288 mmol, 1.5 eq) in portions at room temperature. The resulting mixture was stirred for additional 1 hour at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (15mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30mL), The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: H2O (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 28% B to 46% B in 10 min to afford title compounds. The cyclohexyl diamine ring configuration was assigned based on1H NMR

[0183] 7-bromo-6-{[(1r,4r)-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl]amino}-1- (2,2,2-trifluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile (12.8 mg, 13.51%) as a white solid. LCMS: (ES, m / z): 489.05, 491.05.1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 6.04 (d, J = 7.6 Hz, 1H), 5.60-5.51 (m, 2H), 3.99-3.87 (m, 1H), 3.40-3.34 (m, 2H), 3.24 (s, 3H), 2.59-2.52(m, 2H), 2.42 – 2.32 (m, 1H), 2.20 (s, 3H), 2.03 – 1.91 (m, 2H), 1.80 – 1.71 (m, 2H), 1.51 – 1.27 (m, 4H).

[0184] 7-bromo-6-{[(1s,4s)-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl]amino}-1- (2,2,2-trifluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile (18.3 mg, 19.38%) as yellow oil. LCMS: (ES, m / z): 489.05, 491.05.1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 5.77 (d, J = 6.8 Hz, 1H),5.64-5.49(m, 2H), 5.20-4.07 (m, 1H), 3.45-3.38 (m, 2H), 3.23 (s, 3H), 2.64-2.54 (m, 2H), 2.44-2.39 (m, 1H), 2.22 (s, 3H), 1.93-1.76 (m, 2H), 1.68-1.48 (m, 6H).Compounds below were synthesized following the same method (M1):Cmpd Structure1H NMR LCMS No. [M+H]+3.47(m,1H), 2.99-2.2.87(m,1H), 2.79-2.66(m,1H), 2.33-2.21(m,1H), 201176 5H 169149 7H4H), 1.75-1.65 (m, 2H), 1.57 – 1.27 (m, 5H), 1.27 – 1.07 (m, 4H). 1 7 MH DM 7 11-74 (300 MHz, DMSO-d6) δ 8.75 (s,487.15, 1H), 6.08 (d, J=7.8Hz, 1H), 5.62- 489.15 549 (m 2H) 402 – 386 (m 1H)1-135 (300 MHz, DMSO-d6) δ 8.71 (s,577.10, 1H), 7.52 – 7.43 (m, 2H), 7.33 (t, J579.10 =75 Hz 2H) 727 – 716 (m 1H)1-184 (300 MHz, DMSO-d6) δ 8.77 (s, 572.45, 1H), 7.48 (d, J = 7.1 Hz, 1H), 5.73 574.45 d 71 H 1H 563 5521-210 (300 MHz, DMSO-d6) δ 8.74 (s, 487.20, 1H), 5.95 (d, J = 7.7 Hz, 1H), 5.63 489.20 – 548 2H 439 – 429

[0185] Compounds below were synthesized following the same method (Ml) following the same method with corresponding reactants:1-120 533.3, 535.31-213 537.3, 539.31-110 615.3, 617.31-194 540.0, 542.01-229 517.2, 519.11-124 548.3, 550.31-132 549.3, 551.31-192 529.3, 531.3METHOD 2 (M2)

[0186] Int-2 reacted with amine M2-1 (obtained commercially or synthesized according to methods known in the art) under amide coupling conditions to afford title compound.Examples:Compound 1-155Compound 1-156Step 1: 7-((1r,4R)-4-((7-bromo-2-cyano-1-(2,2,2-trijluoroetiiyl)-l H-imidazo]4,5-c]pyridin- 6-yI)amino)cyclokexyl)-N-((R)-4,5,6, 7-tetrakydropyrazolo[l,5-a]pyridin-4-yl)-7- ara.bicyclo[2.2.1]heptane-2-carbaxamide and 7-((1s,4S)-4-((7-bromo~2-cyano-l-(2,2,2- trijluoroethyl)-lH-imidazo[4, 5-e]pyridin-6-yl)amino)eyclokexyI)-N-((R)-4, 5, 6, 7- tetrakydropyrazolo]1,5-a]pyridin-4-yl)-7-azabicyclo[2.2.1)keptane-2-carboxamide.

[0187] A solution of Inf-2 (100 mg, 0.1 85 mmol, 1 eq), DIEA (72 rag, 0.555 mmol, 3.06 eq) and HATU (1 10 mg, 0.289 mmol, 1.57 eq) in DMF (0.9 mL) was stirred for 15 minutes at room temperature under nitrogen atmosphere. To the above mixture was added (4R)~ 4H,5H.6H,7H-pyrazolo| L5-a]pyndin-4-amine (35 mg, 0.255 mmol, 1.38 eq) dropwise over 2 minutes. The resulting mixture was stirred for additional 20 minutes at room temperature.The reaction was quenched with sat. NaHCO3(aq.) (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 12 mL). The combined organic layers were washed with brine (3x3 mL), dried, over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced, pressure. The crude product (92 mg) was purified by Prep-HPLC with the following conditions Column: XBndge Prep OBD C18 Column. 30*150 mm, 5pm: Mobile Phase A: ILO (l Oramol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 34% B to 51% B in 10 min to afford title compound. The cyclohexyl diamine ring configuration was assigned based on NMR.

[0188] 7-((1r,4R)-4-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridin-6-yl)amino)cyclohexyl)-N-((R)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)- 7-azabicyclo[2.2.1]heptane-2-carboxamide (11.8 mg, 9.59%) as a white solid. LC-MS: (ES, m / z): 660.30; 662.30 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.32 – 8.21 (m, 1H), 7.36 (q, J = 3.1, 2.6 Hz, 1H), 6.01 (dd, J = 31, 1.9 Hz, 1H), 5.99 (q, J = 9 Hz, 1H), 5.54 (q, J = 8.6 Hz, 2H), 5.11 – 4.98 (m, 1H), 4.14 - 3.83 (m, 3H), 3.67 (d, J = 13.5 Hz, 1H), 3.51 - 3.44 (m, 1H), 2.85 – 2.79 (m, 1H), 2.22 - 1.81 (m, 8H), 1.80 - 1.32 (m, 8H), 1.27 - 1.09 (m, 3H).

[0189] 7-((1s,4S)-4-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridin-6-yl)amino)cyclohexyl)-N-((R)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)- 7-azabicyclo[2.2.1]heptane-2-carboxamide (24.3 mg, 19.82%) as a white solid. LC-MS: (ES, m / z): 660.30;662.30 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.25 (dd, J = 8.3, 5.0 Hz, 1H), 7.36 (dd, J = 3.1, 1.8 Hz, 1H), 6.00 (dd, J = 30.7, 1.9, Hz, 1H), 5.84 (dd, J = 7.3, 4.2 Hz, 1H), 5.55 (q, J = 8.6 Hz, 2H), 5.11 – 4.95 (m, 1H), 4.14 – 3.90 (m, 3H), 3.64 (d, J = 15.4 Hz, 1H), 3.40 (s, 1H), 2.92 - 2.83 (m, 1H), 2.39 – 2.31 (m, 1H), 2.16 - 1.89 (m, 5H), 1.77 - 1.50 (m, 10H), 1.49 - 1.17 (m, 3H).

[0190] Compounds below were synthesized following the same method (M2). Cmpd Structure1H NMR LCMS . No [M+H]+, ,1-221 (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 666.30, 7.91 – 7.86 (m, 1H), 6.02 (d, J = 7.6 668.30 H 1H 563 552 2H 415 d , , , ,METHOD 3 (M3)

[0191] Int~3 reacted with aldehyde "M3-1 (obtained commercially or synthesized according to methods known in the art) followed by formaldehyde wider reductive amination conditions to afford the final compound.

[0192] For other set of analogs Inf-3 reacted with acetyl chloride under basic conditions to afford the title nitnle compound.Examples:Compound 1-78Step 1: 7-bro mo-6-{[4-(dhnethylanimo)bicyclo[2.2.2]octan-l-yl]anuno}-l-(2,2,2- trifluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile

[0193] A mixture of Int-3 (86 mg, 0. 194 mmol), STAB (82.256mg, 0,388 mmol) and HCHO (11.65 mg, 0.388 mmol) in THF (1 mL) was stirred for 30 mm at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% FA), 10% to 50% gradient in 10 mm. The crude product (20 mg) was purified by Prep-HPLC with the following conditions Column: Xselect CSH Prep C18 OBD Column, 30* 150mm, Sum;Mobile Phase A: H2O (0 1 % FA), Mobile Phase B: MeCN; Flow rate: 60 mL / ram; Gradient: 12% B to 34% B in 10 min. The resulting mixture rvas concentrated under vacuum to afford title compound (2.7mg.2.93%) as offwvhite solid. LC-MS: (ES, m / z): 471.05.473.05 [M+H], 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.28 (s, 1H), 5.56 (q, J = 8.6 Hz, 2H), 5.36 (s, 1H), 2. 14 (s, 6H), 2.07 (d, J = 8.4 Hz, 6H), 1.65 (t, J = 7.8 Hz, 6H).Compound 1-138Step 1: 7-bromo-6-({4-[(3H-imiday)l-4-ylmethyl)(methyl)amino5bkyclo[2.2.2]oclan-l- yl}am ino)-l-(2,2,2-trljluoroethyl)inudazo[4,5-c]pyrldlne-2-carbonltrile FA salt

[0194] A solution of Int-3 (60 mg, 0. 125 mmol, 1 eq) in DCM(2ml) was treated with 3H- imidazole-4-carbaldehyde (18 mg. 0.187 mmol. 1.50 eq) and STAB (80 mg, 0.377 mmol, 3.02 eq) for 2 hours at room temperature followed by the addition of formaldehyde (8 mg, 0.107 mmol, 0.85 eq, 40'%) in portions at room temperature. The resulting mixture was stirred, for Ihour at room temperature. The reaction was quenched with NaHCO3(aq) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions Column:Xselect CSH Prep C18 OBD Column, 30*150mm, 5um; Mobile Phase A: H2O(0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 6% B to 28% B in 10 min to afford title compound (27.1 mg, 35.88%) as a yellow solid. LCMS: (ES, m / z): 537.05,539.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.22 (s, 1H), 7.51 (d, J = 1.1 Hz, 1H), 6.82 (s, 1H), 5.63 - 5.49 (m, 2H), 5.38 (s, 1H), 3.49 (s, 2H), 2.16 – 2.05 (m, 9H), 1.82 - 1.70 (m, 6H). Compound 1-118

[0195] To a stirred mixture of Int-3 (40 mg, 0.083 mmol, 1 eq) and TEA(84.37 mg, 0.830 mmol, 10 eq) in DCM (1 mL) was added acetyl chloride (19.64 mg, 0.249 mmol, 3 eq) dropwise at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The reaction was quenched by the addition of saturated. NaHCO3(aq.) (5mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 15mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC with the following conditions Column: YMC Triart C18 ExRs, 30*150 mm, 5μm; Mobile Phase A: H2O (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 57% B to 75% B in 10 min. to afford title compound (17.0 mg, 41.97%) as a yellow solid. LCMS: (ES, m / z): 485.05, 487.05.1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.34 (s, 1H), 5.55-5.46 (m, 2H), 5.29 (s, 1H), 2.10-1.97 (m, 6H), 1.97-1.83 (m, 6H), 1.70 (s, 3H). Compounds below were synthesized following the same method (M3):1- (400 MHz, DMSO-d6) δ 8.70 485.05, 118 (s, 1H), 7.34 (s, 1H), 5.55-5.46 487.05 2H 529 1H 210METHOD 4 (M4)

[0196] Int-4 reacted with acyl chloride M4-1 under basic conditions to afford final product.

[0197] For other set of analogs Int-4 reacted with aldehyde M4-2 under reductive amination conditions to afford the title diamine. Examples: Compound 1-113Step 1: 7-bromo-6-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile

[0198] A mixture of Int-4 (100 mg, 0.220 mmol, 1 eq), formaldehyde (7 mg, 0.233 mmol, 1.06 eq) and STAB (140.14 mg, 0.660 mmol, 3 eq) in DCE (5 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NaHCO3(aq.) at room temperature. The resulting mixture was extracted with DCM (2 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min to afford title compound (20 mg, 16.83%) as a white solid. LC-MS (ES, m / z): 431.07; 433.07 [M+H]+.Step 2: N-((1r,4r)-4-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin- 6-yl)amino)cyclohexyl)-N-methylacetamide

[0199] A mixture of 7-bromo-6-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1-(2,2,2- trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile (10 mg, 0.023 mmol, 1 eq), acetyl chloride (3 mg, 0.038 mmol, 1.65 eq) and TEA(7 mg, 0.069 mmol, 2.98 eq) in DCM (1 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The reaction was quenched with H2O at room temperature. The resulting mixture was extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min to afford title compound (1.5 mg, 13.63%) as a white solid. LC-MS: (ES, m / z): 473.15; 475.15 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 6.29-6.00 (m, 1H), 5.71-5.42 (m, 2H), 4.43-3.48 (m, 2H), 2.88-2.67 (m, 3H), 2.06-1.88 (m, 5H), 1.79-1.45 (m, 6H). Compound 1-114

[0200] A mixture of Int-4(50 mg, 0.110 mmol, 1 eq), isocyanatotrimethylsilane (25 mg, 0.217 mmol, 1.97 eq) and TEA(34 mg, 0.336 mmol, 3.05 eq) in DCM (5 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min to afford the crude product. The crude product (30 mg) was purified by Prep-HPLC with the following conditions Column: XBridge Shield RP18 OBD Column19*250 mm; Mobile Phase A: H2O (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 25mL / min; Gradient: 34% B to 52% B in 10 min to afford title compound (10.8 mg, 21.19%) as a white solid. LC-MS: (ES, m / z): 460.15; 462.15 [M+H]+.1H NMR (300 MHz, DMSO−d6) δ ppm 8.75 (s, 1H), 6.10 (d, J = 7.8 Hz, 1H), 5.82 (d, J = 8.1 Hz, 1H), 5.71-5.49 (m, 2H), 5.33 (s, 2H), 4.10-3.81 (m, 1H), 2.02-1.80 (m, 4H), 1.58-1.39 (m, 2H), 1.33-1.12 (m, 3H).Compounds below were synthesized following the same method: Cm Structure1H NMR LCMS pd. [M+H]+NMETHOD 5 (M5)

[0201] Int-5 converted into title nitrile via reductive amination of carbonyl compound M5- 1 (obtained commercially or synthesized according to methods known in the art) in the presence of reducing agents such as sodium tri acetoxy borohydride. Compounds were purified by prep-HPLC.Examples:Compound XStep 1: 7-bromo-6-((3-chloro-5-cyanobenjyl)amino)-l-(2,2,2-trifliioroethyI)-lH- imidazo[4,5-c]pyridine-2-carbonitrile

[0202] To a solution of 6-amino-7-bromo-l-(2,2,2-trifluoroethyl)imidazo[4,5-c]pyridine-2- carbonitrile (20 mg, 62.49 μmol) 3-chloro-5-formyl-benzonitrile (20.69 mg, 124.97 μmol) in DCM (1 mL) was added TFA (54.15 mg, 474.90 μmol), the mixture was stirred at 25 °C for 2 h, then NaBH(OAc)3(66.22 mg, 312.43 μmol) was added into the mixture. The mixture was stirred at 25 °C for 10 h. LC-MS showed 32% desired compound. The reaction was filtered, and the filtrate was concentrated under vacuum The residue was purified by prep-HPLC TFA condition; column: Phenomenex Luna C18 75 x 30mm x 3um; mobile phase: [H2O (0.1% TFA)-MeCN]; gradient: 45%-75% B over 8.0 min to afford title compound (7.63 mg, 24.43% yield) as a pale yellow amorphous solid. LCMS (ES, m / z): 469.1 / 471.1 [M+H]+.NMR (400 MHz, MeOH-d4) δ ppm 8.59 (s, 1 H), 7.67 (d, J =1.63 Hz, 1 H), 7.63 (s, 2 H), 5.52 (q, J =8.17 Hz, 2 H), 4.77 (s, 2 H).

[0203] Compounds below were synthesized following the same method (M5) employing parallel synthesis approach:1-232 476.2, 478.2

[0204] In some cases, Int-5 was converted into amides or carbamides under standard amide coupling or urea formation conditions. Compound 1-57Step 1: 1(7bromo2cyano1(2,2,2trifluoroethyl)1Himidazo[4,5c]pyridin6yl)3(1- methylpiperidin-4-yl)urea

[0205] A solution of 6-amino-7-bromo-1-(2,2,2-trifluoroethyl)imidazo[4,5-c]pyridine-2- carbonitrile (95 mg, 0.297 mmol, 1 eq) and CDI (480 mg, 2.960 mmol, 9.97 eq) in 1,4- dioxane (13 mL) was stirred for 4 hours at 100°C under nitrogen atmosphere. The mixturewas allowed to cool down to room temperature. To the above mixture was added 1- methylpiperidin-4-amine (340 mg, 2.977 mmol, 10.03 eq) dropwise over 2min at room temperature. The resulting mixture was stirred for additional 40min at room temperature. The reaction was quenched with sat. NaHCO3(aq.) (2mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 12mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (29mg) was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: H2O (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% B to 13% B in 9 min to get title compound (3.3 mg, 2.35%) as a white solid. LCMS (ES, m / z): 460.0, 462.0 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.26 (s, 1H), 8.15 (d, J = 6.6 Hz, 1H), 5.76-5.63 (m, 2H), 3.65-3.50 (m, 1H), 2.65 (d, J = 10.8 Hz, 2H), 2.17 (s, 3H), 2.08-2.01 (m, 2H), 1.86-1.81 (m, 2H), 1.55 – 1.44 (m, 2H). Compound 1-52

[0206] A solution of 6-amoino-7-bromo-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine- 2-carbonitrile (100 mg, 0.312 mmol, 1 eq), 1-methylpiperidine-4-carbonyl chloride (250 mg, 1.547 mmol, 4.95 eq) in pyridine (4 mL) was added and stirred at 110 °C for 2 hours. The solution was diluted with EtOAc and extracted with H2O. The H2O was concentrated under vacuum. The residue was purified by flash chromatography on C18 gel eluting with acetonitrile / H2O (25:75) to afford crude product. The crude product was purified by Prep- HPLC with following conditions: Column: Xselect CSH OBD, 30*150mm, 5um; Mobile Phase A: H2O (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 6% B to 12% B in 10 min to afford title compound (38.6 mg, 23.04%) as a yellow solid. LC-MS: (ESI, m / z): 445.00, 447.00 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.49 (br,1H), 9.11 (s, 1H), 5.85-5.70 (m, 2H), 3.62-3.51 (m, 2H), 3.10-2.95 (m, 2H), 2.80 (s, 3H), 2.79-2.65 (m, 1H), 2.15-2.05 (m, 2H), 1.90-1.70 (m, 2H). METHOD 6 (M6)(obtained commercially or synthesized according to methods known in the art) under Pd- catalyzed or SNAr conditions. Nitro group in compound M6-3 was reduced and diamine M6- 4 was subjected to cyclization via 4,5-dichloro-1,2,3-dithiazol-2-ylium chloride in pyridine. Intermediate M6-5 was brominated or iodinated by treatment with NBS or iodine yielding title nitrile. In case of Boc-protected amines additional step of HCl or TFA mediated deprotection was performed to provide final product. Examples: Compound 1-140Step 1: tert-butyl ((1r,4S)-4-((5-nitro-4-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate

[0208] A solution of tert-butyl ((1r,4S)-4-aminocyclohexyl)((S)-tetrahydrofuran-3- yl)carbamate (800 mg, 2.813 mmol, 1.00 eq) and 2-bromo-5-nitro-N-(2,2,2- trifluoroethyl)pyridin-4-amine (840 mg, 2.800 mmol, 1.00 eq), TEA(851 mg, 8.410 mmol, 3.00 eq) in DMA (10 mL) was stirred for overnight at 120°C under nitrogen atmosphere. The reaction was quenched with saturated NaHCO3aqueous at room temperature. The resulting mixture was extracted with EtOAc (3 x50 mL). The combined organic layers were washed with saturated NaCl aqueous and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (3:1) to afford title compound (1.4 g, 89.38%) as a yellow oil. LCMS (ES, m / z): 504.25[M+H]+. Step 2: of tert-butyl ((1r,4S)-4-((5-amino-4-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate

[0209] To a solution of tert-butyl ((1r,4S)-4-((5-nitro-4-((2,2,2- trifluoroethyl)amino)pyridin-2-yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate (1.3 g, 2.582 mmol, 1 eq) in EtOAc (20 mL) was added Pd / C (150 mg, 0.141 mmol, 0.05 eq, 10%) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 8 hours under hydrogen atmosphere using a hydrogen balloon. Then the solution was filtered through a Celite pad and concentrated under reduced pressure to afford title compound (1 g, 73.61%) as a purple solid. LCMS (ES, m / z): 474.25[ M+H]+. Step 3: tert-butyl ((1r,4S)-4-((5-(((Z)-4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino)-4- ((2,2,2-trifluoroethyl)amino)pyridin-2-yl)amino)cyclohexyl)((S)-tetrahydrofuran-3- yl)carbamate

[0210] A solution of tert-butyl ((1r,4S)-4-((5-amino-4-((2,2,2-trifluoroethyl)amino)pyridin- 2-yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate (1.1 g, 2.323 mmol, 1 eq) and 4,5-Dichloro-1,2,3-dithiazol-2-ylium chloride (700 mg, 3.357 mmol, 1.45 eq) in DCM (30 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / MeOH (10:1) to afford title compound (800 mg, 42.74%) as a brown solid. LCMS (ES, m / z): 609.15[ M+H]+. Step 4: tert-butyl ((1r,4S)-4-((2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate

[0211] A solution of tert-butyl ((1r,4S)-4-((5-(((Z)-4-chloro-5H-1,2,3-dithiazol-5- ylidene)amino)-4-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)amino)cyclohexyl)((S)- tetrahydrofuran-3-yl)carbamate (700 mg, 1.149 mmol, 1 eq) in pyridine (20 mL) was stirredfor overnight at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min to afford title compound (400 mg, 58.18%) as a purple oil. LCMS (ES, m / z): 509.25[ M+H]+. Step 5: tert-butyl ((1r,4S)-4-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridin-6-yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate

[0212] A solution of tert-butyl ((1r,4S)-4-((2-cyano-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridin-6-yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate (400 mg, 0.787 mmol, 1 eq) and NBS (140 mg, 0.787 mmol, 1.00 eq) in MeCN (10 mL) was stirred for 1 hour at room temperature. The reaction was quenched with saturated Na2SO3aqueous at room temperature. The resulting mixture was extracted with DCM (3 x50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min to afford title compound (300 mg, 58.43%) as a purple solid. LCMS (ES, m / z): 587.15,589.15 [ M+H]+. Step 6: 7-bromo-6-(((1S,4r)-4-(((S)-tetrahydrofuran-3-yl)amino)cyclohexyl)amino)-1- (2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile

[0213] A solution of tert-butyl ((1r,4S)-4-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridin-6-yl)amino)cyclohexyl)((S)-tetrahydrofuran-3-yl)carbamate (260 mg, 0.443 mmol, 1 eq) in HCl(gas) in 1,4-dioxane (4.0M,8 mL) was stirred for 6 hours at room temperature. The precipitated solids were collected by filtration and washed with 1,4-dioxane (3 x 10mL) to afford title compound (196.3 mg, 83.32%) as a brown solid. LCMS (ES, m / z): 487.25,489.25[ M+H]+;1H NMR (300 MHz, DMSO-d6) δ 9.30 – 9.18 (m, 2H), 8.77 (s, 1H), 6.26-2.11 (m, 1H), 5.57 (q, J = 8.6 Hz, 2H), 4.05 – 3.78 (m, 5H), 3.72-3.61 (m, 1H), 3.08- 2.95 (m, 1H), 2.33 – 2.13 (m, 3H), 2.12 – 1.95 (m, 3H), 1.65-1.40 (m, 4H).

[0214] Compounds below were synthesized following the same method (M6): Cmpd. Structure1H NMR LCMS [M+H]+1-44 (300 MHz, Chloroform-d) δ ppm 417.1, 419.1 8.67 (s, 1H), 7.37-7.26 (m, 1H),Other Methods Compound 1-116hydroxycyclopentyl](methyl)amino}cyclohexyl]amino}-1-(2,2,2-trifluoroethyl)imidazo[4,5- c]pyridine-2-carbonitrile.

[0215] A mixture of 7-bromo-6-{[(1r,4r)-4-{[(1S,2S)-2- hydroxycyclopentyl]amino}cyclohexyl]amino}-1-(2,2,2-trifluoroethyl)imidazo[4,5- c]pyridine-2-carbonitrile (20 mg, 0.040 mmol, 1 eq) and HCHO (2.40 mg, 0.080 mmol, 2.00 eq) and STAB (25 mg, 0.118 mmol, 2.96 eq) in DCE (1 mL) was stirred for 24 hours at room temperature under air atmosphere. The reaction was quenched with H2O at room temperature. The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with H2O (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% FA), 10% to 50% gradient in 10 min to afford title compound (11.1 mg, 53.07%) as a off-white solid. LC-MS (ES, m / z):515.20517.20[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.31 (s, 1H), 6.09 (d, J = 8.0 Hz, 1H), 5.62 – 5.51 (m, 2H), 3.99 – 3.90 (m, 2H), 2.92 – 2.82 (m, 3H), 2.25 (s, 3H), 2.01 – 1.92 (m, 2H), 1.86 – 1.71 (m, 4H), 1.66 – 1.49 (m, 2H), 1.50 – 1.38 (m, 6H).Compound 1-204Step 1: N-(3-((7-bromo-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)bicyclo[1.1.1]pentan-1-yl)acetamide

[0216] A solution of 6-({3-aminobicyclo[1.1.1]pentan-1-yl}amino)-7-bromo-1-(2,2,2- trifluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile (100 mg, 0.249 mmol, 1 eq), acetyl chloride (40 mg, 0.510 mmol, 2.04 eq) and TEA(75 mg, 0.741 mmol, 2.97 eq) in DCM (10 mL) was stirred for 1 hour at room temperature. The reaction was quenched with saturated NaHCO3aqueous (3x10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were concentrated. Dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min to afford title compound (28.3 mg, 25.10%) as a white solid. LCMS (ES, m / z): 442.95,445.95 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.44 (s, 1H), 7.17 (s, 1H), 5.65-5.47 (m, 2H), 2.34 (s, 6H), 1.78 (s, 3H). Compound 1-84 Compound 1-85Step 1: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-7-chloro-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile

[0217] A mixture of 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile (440 mg, 1.154 mmol, 1 eq) and NCS (169.47 mg, 1.269 mmol, 1.1 eq) in MeCN (5 mL) was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% FA), 10% to 50% gradient in 50 min to afford title compound (260 mg, 54.20%) as a yellow solid. LC-MS (ES, m / z): 415.0; 416.0 [M+H]+. Step 2: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-7-chloro-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile

[0218] A mixture of 7-chloro-6-{1,4-dioxaspiro[4.5]decan-8-ylamino}-1-(2,2,2- trifluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile (200 mg, 0.481 mmol, 1 eq) in TFA (5mL)was stirred for overnight at room temperature. The residue was neutralized to pH 7 with saturated NaHCO3(aq.). The aqueous layer was extracted with DCM (3x20 mL). The combined organic layers were concentrated under reduced pressure to afford title compound (120 mg, 67.11%) as a yellow solid. LC-MS (ES, m / z): 371.1; 372.1 [M+H]+. Step 3: 7-((1r,4r)-4-((7-chloro-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide and 7-((1s,4s)-4-((7-chloro-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide

[0219] A mixture of 7-chloro-6-((4-oxocyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile (60 mg, 0.081 mmol, 1 eq), N-(2-methoxyethyl)-7- azabicyclo[2.2.1]heptane-2-carboxamide (32.00 mg, 0.162 mmol, 2 eq), STAB (51.31 mg, 0.243 mmol, 3 eq) and TFA (55.21 mg, 0.486 mmol, 6 eq) in DCM (4 mL) was stirred for overnight at room temperature. After concentration. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% FA), 10% to 50% gradient in 10 min. Isomers separated by Prep- HPLC with the following conditions Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5m; Mobile Phase A: H2O (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 32% B to 42% B in 10 min to afford title compound. The stereochemistry of both isomers was assigned based on1H NMR.

[0220] 7-((1r,4r)-4-((7-chloro-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridin-6-yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2- carboxamide (6.6 mg, 14.76%) as a white solid. LCMS (ES, m / z): 554.20, [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.85 (t, J = 5.5 Hz, 1H), 6.25 (d, J = 7.8 Hz, 1H), 5.51 (q, J = 8.6 Hz, 2H), 4.05 – 3.85 (m, 1H), 3.69 – 3.61 (m, 1H), 3.51 – 3.42 (m,2H), 3.28 – 3.17 (m, 6H), 2.88 – 2.79 (m, 1H), 2.18 – 2.01 (m, 2H), 1.92 – 1.87 (m, 2H), 1.72 – 1.68 (m, 2H), 1.54 – 1.33 (m, 5H), 1.27 – 1.13 (m, 4H).

[0221] 7-((1s,4s)-4-((7-chloro-2-cyano-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5- c]pyridin-6-yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2- carboxamide (11.7 mg, 26.17%) as a white solid. LCMS (ES, m / z): 554.20 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.84 (t, J = 5.6 Hz, 1H), 6.10 (d, J = 7.3 Hz, 1H), 5.52 (q, J = 8.6 Hz, 2H), 4.19 – 4.01 (m, 1H), 3.69 – 3.61 (m, 1H), 3.50 – 3.40 (m, 2H), 3.30 – 3.19 (m, 6H), 2.85 – 2.76 (m, 1H), 2.41 – 2.32 (m, 1H), 1.95 – 1.85 (m, 2H), 1.79 – 1.51 (m, 9H), 1.45 – 1.19 (m, 3H). Example 3. Preparation of 5-Azabenzimidazoles with differentiated N1-substitution Compound 1-48

[0222] To a solution of 2,4-dibromo-5-nitro-pyridine (3 g, 10.64 mmol, 1 eq) in DMF (60 mL) were added 1,1,1-trifluoropropan-2-amine (2.41 g, 21.28 mmol, 11.16 uL, 2 eq) and DIEA (2.75 g, 21.28 mmol,3.71 mL, 2 eq). The mixture was stirred at 70 °C for 16 hr. The reaction mixture was concentrated, the residue was diluted with H2O (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~6% EtOAc / petroleum ether gradient @ 100 mL / min) to afford title compound (1.6 g, 47.87% yield) as a green solid.1HNMR (400 MHz, MeCN-d3) δ ppm 1.50 (d, J=6.78 Hz, 3 H) 4.49 - 4.70 (m, 1 H) 7.30 (s, 1 H) 8.02 (br d, J=5.65 Hz, 1 H) 8.92 (s, 1 H). Step 2: N2-(1-methyl-4-piperidyl)-5-nitro-N4-(2,2,2-trifluoro-1-methylethyl)pyridine-2,4- diamine

[0223] To a solution of 2-bromo-5-nitro-N-(2,2,2-trifluoro-1-methyl-ethyl)pyridin-4-amine (60 mg, 191.05 umol, 1 eq) in dioxane (2 mL) were added 1-methylpiperidin-4-amine (65.45 mg, 573.14 umol, 3 eq) Cs2CO3(93.37 mg, 286.57 umol, 1.5 eq) and 1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-2H-imidazole;3-chloropyridine;dichloropalladium (15.16 mg, 19.10 umol, 0.1 eq). The mixture was stirred at 110 °C for 16 hr. The reaction mixture was concentrated, and residue was diluted in H2O (10 mL) and extracted with EtOAc (30 mL× 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude product (663.57 mg, crude) was used in next step directly. Step 3: N2-(1-methyl-4-piperidyl)-N4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine-2,4,5- triamine

[0224] To a solution of N2-(1-methyl-4-piperidyl)-5-nitro-N4-(2,2,2-trifluoro-1-methyl- ethyl)pyridine-2,4-diamine (663.57 mg, 1.91 mmol, 1 eq) in EtOH (20 mL) and H2O (5 mL) was added Fe (533.45 mg, 9.55 mmol, 5 eq) and NH4Cl (510.96 mg, 9.55 mmol, 5 eq). The mixture was stirred at 70 °C for 16 hr. The reaction mixture was concentrated, and the residue was purified by prep-HPLC neutral condition, column: Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O(NH4HCO3)-MeCN]; B%: 5%-40%,8min to afford title compound (110 mg, 18.14% yield) as a black solid. Step 4: 6-[(1-methyl-4-piperidyl)amino]-1-(2,2,2-trifluoro-1-methyl-ethyl)imidazo[4,5- c]pyridine-2-carbonitrile

[0225] To a solution of N2-(1-methyl-4-piperidyl)-N4-(2,2,2-trifluoro-1-methyl- ethyl)pyridine-2,4,5-triamine (65 mg, 204.82 umol, 1 eq) in Py (6.5 mL) was added 4,5- dichlorodithiazol-2-ium;chloride (34.17 mg, 163.86 umol, 0.8 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. And then the reaction mixture was stirred at 60 °C for 16 hr. The reaction mixture was concentrated, and the residue was purified by prep-HPLC neutral condition, column: Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(NH4HCO3)-MeCN]; B%: 20%-50%,8min to afford title compound (16 mg, 22.17% yield) as a black solid. Step 5: 7-bromo-6-[(1-methyl-4-piperidyl)amino]-1-(2,2,2-trifluoro-1-methyl- ethyl)imidazo[4,5-c]pyridine-2-carbonitrile

[0226] To a solution of 6-[(1-methyl-4-piperidyl)amino]-1-(2,2,2-trifluoro-1-methyl- ethyl)imidazo[4,5-c]pyridine-2-carbonitrile (15 mg, 42.57 umol, 1 eq) in MeCN (0.5 mL) was added NBS (7.58 mg, 42.57 umol, 1 eq). The mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated, and the residue was purified by prep-HPLC TFA condition, column: Phenomenex Luna C18100*30mm*5um; mobile phase: [H2O(TFA)- MeCN]; B%: 20%-50%, 8min to afford title compound (1.1 mg, 4.34% yield) as a yellow oil.1H NMR (400 MHz, MeCN-d3) δ ppm 1.23 - 1.35 (m, 1 H) 1.85 - 1.90 (m, 1 H) 2.07 (br d, J=7.25 Hz, 3 H) 2.77 (s, 3 H) 2.81 (br s, 1 H) 3.03 (br t, J=12.57 Hz, 2 H) 3.52 (br d, J=11.88 Hz, 2 H) 4.20 - 4.37 (m, 1 H) 5.63 (br d, J=7.25 Hz, 1 H) 6.46 - 6.63 (m, 1 H) 8.65 (s, 1 H) 10.51 (br s, 1 H). Compound 1-80 Compound 1-81

[0227] A mixture of 2,4-dibromo-5-nitropyridine (5 g, 17.737 mmol, 1 eq), 2,2- difluoroethan-1-amine (2.16 g, 26.605 mmol, 1.5 eq) and TEA (5.38 g, 53.211 mmol, 3 eq) in THF (500 mL) was stirred for 2 hours at 40°C. The solution was concentrated, and the residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (8:1) to afford title compound (4.6 g, 91.95%) as a yellow solid. LCMS (ES, m / z): 282.20 [M+H]+. Step 2: N4-(2,2-difluoroethyl)-5-nitro-N2-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine-2,4- diamine

[0228] A mixture of 2-bromo-N-(2,2-difluoroethyl)-5-nitropyridin-4-amine (4.6 g, 16.309 mmol, 1 eq), 1,4-dioxaspiro[4.5]decan-8-amine (3.85 g, 24.464 mmol, 1.5 eq) and TEA(4.95g, 48.927 mmol, 3 eq) in DMF (100 mL) was stirred for 2 hours at 90°C. The resulting mixture was quenched with H2O and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with H2O (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1:1) to afford title compound (4.854 g, 83.05%) as a yellow solid. LCMS (ES, m / z): 359.35 [M+H]+. Step 3: N4-(2,2-difluoroethyl)-N2-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine-2,4,5-triamine

[0229] A mixture of N4-(2,2-difluoroethyl)-5-nitro-N2-(1,4-dioxaspiro[4.5]decan-8- yl)pyridine-2,4-diamine (2.4 g, 6.697 mmol, 1 eq), tetrahydroxydiborane (1.80 g, 20.091 mmol, 3 eq) and 2-(pyridin-2-yl)pyridine (1.05 g, 6.697 mmol, 1 eq) in DMF (30 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (8:1) to afford title compound (2 g, 90.94%) as a purple solid. LCMS (ES, m / z): 329.19 [M+H]+. Step 4: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-1-(2,2-difluoroethyl)-1H-imidazo[4,5- c]pyridine-2-carbonitrile

[0230] A mixture of N4-(2,2-difluoroethyl)-N2-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine- 2,4,5-triamine (1.8 g, 5.482 mmol, 1 eq) and 4,5-dichloro-1,2,3-dithiazol-1-ium (1.26 g, 6.030 mmol, 1.1 eq) in DCM (12 mL) was stirred for 1 hours at room temperature. The resulting mixture was concentrated under reduced pressure and dissolved in pyridine (12 mL) and DMF (12 mL). The solution was stirred for 2 hours at 50°C. The crude product was purified by reverse phase flash (MeCN:H2O=2:3) to afford title compound (634 mg, 31.83%) as a purple solid. LCMS (ES, m / z): 364.19 [M+H]+. Step 5: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-7-bromo-1-(2,2-difluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile

[0231] A mixture of 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-1-(2,2-difluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile (730 mg, 2.009 mmol, 1 eq) and NBS (357.57 mg, 2.009 mmol, 1 eq) in MeCN (5 mL) was stirred for 2 hours at room temperature. The reaction was quenched by the addition of Na2SO3aq. (2mL) at 0°C. The mixture was concentrated and purified by reverse phase flash (MeCN:H2O=2:3) to afford title compound (346 mg, 38.94%) as a yellow solid. LCMS (ES, m / z): 441.19 [M+H]+. Step 6: 7-bromo-1-(2,2-difluoroethyl)-6-((4-oxocyclohexyl)amino)-1H-imidazo[4,5- c]pyridine-2-carbonitrile

[0232] A mixture of 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-7-bromo-1-(2,2- difluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile (170 mg, 0.384 mmol, 1 eq) in TFA (2 mL) was stirred for 2hours at room temperature. The resulting mixture was concentrated and then dissolved in Na2CO3aqueous. The mixture was extracted with DCM (3 x 5mL). The combined organic layers were washed with H2O (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to afford crude title compound (160 mg) as a yellow solid. LCMS (ES, m / z): 398.19 [M+H]+. Step 7: 7-((1r,4r)-4-((7-bromo-2-cyano-1-(2,2-difluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide and 7-((1s,4s)-4-((7-bromo-2-cyano-1-(2,2-difluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide

[0233] A solution of 7-bromo-1-(2,2-difluoroethyl)-6-((4-oxocyclohexyl)amino)-1H- imidazo[4,5-c]pyridine-2-carbonitrile (80 mg, 0.201 mmol, 1 eq), N-(2-methoxyethyl)-7- azabicyclo[2.2.1]heptane-2-carboxamide (119.49 mg, 0.603 mmol, 3 eq) in THF (2 mL) was treated with Et3N (30.49 mg, 0.301 mmol, 1.5 eq) for 1 hours at room temperature followed by the addition of STAB (127.73 mg, 0.603 mmol, 3 eq) in portions at room temperature. The crude product was purified by reverse phase flash (MeCN:H2O=2:3) and further purification by Prep-HPLC with the following conditions Column: XBridge Prep Phenyl OBD 19*250 mm, 5m; Mobile Phase A: H2O(10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 42% B to 52% B in 10 min. The resulting mixture was concentrated under vacuum. The stereochemistry of both isomers was assigned based on1H NMR.

[0234] 7-((1r,4r)-4-((7-bromo-2-cyano-1-(2,2-difluoroethyl)-1H-imidazo[4,5-c]pyridin- 6-yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide (7.2 mg, 6.17%) as a yellow solid. LCMS (ES, m / z): 580.10, 582.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.92 – 8.49 (m, 1H), 8.11 – 7.62 (m, 1H), 6.83 – 6.24 (m, 1H), 6.10 – 5.80 (m, 1H), 5.10 (t, J = 9.0 Hz, 2H), 4.05 – 3.85 (m, 1H), 3.75 – 3.65 (m, 1H), 3.45 – 3.40 (m, 1H), 3.29 – 3.20 (m, 7H), 2.85 – 2.70 (m, 1H), 2.49 – 2.45 (m, 2H), 2.20 – 1.80 (m, 5H), 1.74 – 1.60 (m, 2H), 1.54 – 1.12 (m, 8H).

[0235] 7-((1s,4s)-4-((7-bromo-2-cyano-1-(2,2-difluoroethyl)-1H-imidazo[4,5-c]pyridin- 6-yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide (14.8 mg, 12.69%) as a yellow solid. LCMS (ES, m / z): 580.10, 582.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.98 – 7.61 (m, 1H), 6.83 – 6.30 (m, 1H), 5.78 (d, J =6.0 Hz, 1H), 5.10 (t, J = 9.0 Hz, 2H), 4.21 – 4.05 (m, 1H), 3.68 – 3.60 (m, 1H), 3.41 – 3.40 (m, 1H), 3.29 – 3.28 (m, 3H), 3.22 – 3.20 (m, 4H), 2.85 – 2.72 (m, 1H), 2.40 – 2.30 (m, 1H), 1.93 – 1.80 (m, 2H), 1.75 – 1.50 (m, 9H), 1.48 – 1.18 (m, 3H). Compound 1-75 Compound 1-76Step 1: 2-bromo-N-(2-fluoroethyl)-5-nitropyridin-4-amine

[0236] To a stirred solution of 2,4-dibromo-5-nitropyridine (3 g, 10.64 mmol) and 2- fluoroethanamine hydrochloride (1.14 g, 11.49 mmol) in THF (15 mL) was added TEA (4.32 g, 42.67 mmol) in portions at room temperature. The reaction mixture was adjusted to pH = 7 with NaHCO3(aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford crude (3.0 g) title compound crude. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): 263.97 [M+H]+. Step 2: 6-bromo-N4-(2-fluoroethyl)pyridine-3,4-diamine

[0237] To a stirred solution of 2-bromo-N-(2-fluoroethyl)-5-nitropyridin-4-amine (8 g, 30.29 mmol) and B2(OH)4 (10.86 g, 121.13 mmol) in DMF (100 mL) were added 4,4'- bipyridine (236 mg, 1.51 mmol) in portions at 0°C. The resulting mixture was stirred for additional 10min at room temperature. The reaction mixture was adjusted to pH = 7 with NaHCO3(aq.) and extracted with EtOAc for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel columnchromatography, eluted with DCM / MeOH (9:1) to afford title compound (4 g, 56.40%) as a red solid. LCMS (ES, m / z): 307.97 [M+H]+. Step 3: 6-bromo-N3-[(5E)-4-chloro-1,2,3-dithiazol-5-ylidene]-N4-(2-fluoroethyl)pyridine- 3,4-diamine

[0238] A solution of 6-bromo-N4-(2-fluoroethyl)pyridine-3,4-diamine (4 g, 17.08 mmol) and dichloro-1lambda4,2,3-dithiazol-1-ylium chloride (5.34 g, 25.63 mmol) in DMF (40 mL) was stirred for 1 hour at room temperature. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (9:1) to afford title compound (4 g, 63.32%) as a yellow solid. LCMS (ES, m / z): 368.90 [M+H]+. Step 4: 6-bromo-1-(2-fluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile

[0239] To a stirred solution of 6-bromo-N3-[(5E)-4-chloro-1,2,3-dithiazol-5-ylidene]-N4- (2-fluoroethyl)pyridine-3,4-diamine (1.1 g, 2.97 mmol) in DMF (10 mL) was added HCl(gas)in 1,4-dioxane (325.48 mg, 8.92 mmol) in portions at 80°C.The resulting mixture was stirred for additional 2 hourss at 80°C. The reaction mixture was adjusted to pH = 7 with NaHCO3(aq.) and extracted with EtOAc for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20:1) to afford title compound (110 mg, 13.74%) as a yellow solid. LCMS (ES, m / z): 268.98 [M+H]+. Step 5: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-1-(2-fluoroethyl)-1H-imidazo[4,5- c]pyridine-2-carbonitrile

[0240] A mixture of 6-bromo-1-(2-fluoroethyl)-1H-imidazo[4,5-c]pyridine-2-carbonitrile (300 mg, 1.119 mmol, 1 eq), 1,4-dioxaspiro[4.5]decan-8-amine (350 mg, 2.238 mmol, 2 eq), Dppf Pd G3 (153 mg, 0.167 mmol, 0.15 eq), Dppf (125 mg, 0.2238 mmol, 0.20 eq) and Cs2CO3(1093 mg, 3.357 mmol, 3.00 eq) in1,4-dioxane (10 mL) was stirred for 2 hours at 100°C under nitrogen atmosphere. The reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc. Then the combined organic phase was washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% FA), 10% to 50% gradient in 30 min to afford the title compound (50 mg, 12.9%) as a yellow solid. LC-MS (ES, m / z): 346.2 [M+H]+. Step 6: 6-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-7-bromo-1-(2-fluoroethyl)-1H- imidazo[4,5-c]pyridine-2-carbonitrile

[0241] A solution of 6-{1,4-dioxaspiro[4.5]decan-8-ylamino}-1-(2- fluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile (50 mg, 0.145 mmol, 1 eq) and NBS (20.61 mg, 0.116 mmol, 0.8 eq) in MeCN (2 mL) was stirred for 1 hour at room temperature. The reaction was quenched with sat. Na2SO3(aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 15mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude title compound (50 mg) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): 423.01 [M+H]+. Step 7: 7-bromo-1-(2-fluoroethyl)-6-((4-oxocyclohexyl)amino)-1H-imidazo[4,5-c]pyridine- 2-carbonitrile

[0242] A solution of 7-bromo-6-{1,4-dioxaspiro[4.5]decan-8-ylamino}-1-(2- fluoroethyl)imidazo[4,5-c]pyridine-2-carbonitrile (50 mg, 0.118 mmol, 1 eq) and TFA (2 mL) in DCM (2 mL) was stirred for 2 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% FA), 10% to 40% gradient in 10 min to afford title compound (24 mg, 49.81%) as a yellow solid. LCMS (ES, m / z): 379.04 [M+H]+. Step 8: 7-((1r,4r)-4-((7-bromo-2-cyano-1-(2-fluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide and 7-((1s,4s)-4-((7-bromo-2-cyano-1-(2-fluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide

[0243] A solution of 7-bromo-1-(2-fluoroethyl)-6-[(4-oxocyclohexyl)amino]imidazo[4,5- c]pyridine-2-carbonitrile (20 mg, 0.053 mmol, 1 eq) and N-(2-methoxyethyl)-7- azabicyclo[2.2.1]heptane-2-carboxamide (12.51 mg, 0.064 mmol, 1.2 eq),STAB (33.44 mg, 0.159 mmol, 3 eq) in DCM (2 mL) was stirred for 3 hours at room temperature. The reaction was quenched with saturated NaHCO3aqueous at 0ºC.The resulting mixture was extracted with DCM (3 x 5mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (19mg) was purified by Prep-HPLC with the following conditions Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5μm; Mobile Phase A: H2O (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 22% B to 44% B in 10 min to get title compound. The stereochemistry of both isomers was assigned based on1H NMR.

[0244] 7-((1r,4r)-4-((7-bromo-2-cyano-1-(2-fluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide(1.4 mg, 4.72%) as a white solid. LCMS (ES, m / z): 562.35, 564.35 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.86 (t, J = 5.7 Hz, 1H), 5.83 (d, J = 7.9 Hz, 1H), 4.91 (s, 2H), 4.85 – 4.73 (m, 2H), 4.02-3.91 (m, 1H), 3.65-3.50 (m, 1H), 3.55-3.41 (m, 2H), 3.30-3.19 (m, 5H), 2.85-2.75 (m, 1H), 2.20-1.82(m, 4H), 1.73-1.65(m,2H), 1.59-1.12(m, 9H).

[0245] 7-((1s,4s)-4-((7-bromo-2-cyano-1-(2-fluoroethyl)-1H-imidazo[4,5-c]pyridin-6- yl)amino)cyclohexyl)-N-(2-methoxyethyl)-7-azabicyclo[2.2.1]heptane-2-carboxamide (1.3 mg, 4.38%) as a white solid. LCMS (ES, m / z): 562.35, 564.35 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.85 (t, J = 5.5 Hz, 1H), 5.69 (d, J = 7.4 Hz, 1H), 4.92 (s, 2H), 4.86 – 4.74 (m, 2H), 4.19-4.09 (m, 1H), 3.61-3.52 (m, 1H), 3.33-3.19 (m, 6H), 2.86-2.71 (m, 1H), 2.39-2.31 (m, 1H), 1.93-1.74 (m, 3H), 1.71 – 1.50 (m, 9H), 1.44 – 1.16 (m, 4H).

[0246] Compounds below were synthesized following the same method as Compound 1- 75 and Compound 1-76 starting with 2,4-dibromo-5-nitropyridine and corresponding amine, and relative stereochemistry of centers on cyclohexyl ring was assigned based on1H NMR: Cmpd. Structure1H NMR LCMS No [M+H]+Example 4. Preparation of Benzimidazoles Compound 1-45 Compound 1-46Step 1: 2-bromo-3-fluoro-6-nitro-N-(2,2,2-trifluoroethyl)aniline

[0247] A solution of 2-bromo-1,3-difluoro-4-nitrobenzene (300.00 mg, 1.26 mmol, 1.00 eq.) and 2,2,2-trifluoroethyl-1-amine (374.60 mg, 3.73 mmol, 3.00 eq.), DIEA (488.77 mg, 3.78 mmol, 3.00 eq.) in THF (3 mL) was stirred for 4 hours at room temperature. The resulting mixture was stirred for 4 hours at 80 °C under nitrogen atmosphere. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The aqueous layer was extracted with EtOAc (3x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (19:1) to afford title compound (350 mg, 87.58%) as yellow oil. LC-MS (ES, m / z): 316.95; 318.95 [M+H]+. Step 2: N1-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-bromo-4-nitro-N3-(2,2,2- trifluoroethyl)benzene-1,3-diamine

[0248] A solution of 2-bromo-3-fluoro-6-nitro-N-(2,2,2-trifluoroethyl)aniline (350.00 mg, 1.10 mmol, 1.00 eq.) and 4-{2-oxa-6-azaspiro[3.3]heptan-6-yl}cyclohexan-1-amine (433.40 mg, 2.21 mmol, 2.00 eq.), DIEA (428.05 mg, 3.31 mmol, 3.00 eq.) in NMP (3.5 mL) was stirred for 2.5 hours at 100 °C under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the following conditions: (column, C18 silica gel; mobilephase, MeCN / H2O (10 mmol / L NH4HCO3) (11:9) to afford title compound (600 mg, 99.15%) as a yellow solid. LC-MS (ES, m / z): 493.10; 495.10 [M+H]+. Step 3: of N4-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-3-bromo-N2-(2,2,2- trifluoroethyl)benzene-1,2,4-triamine

[0249] To a stirred solution of N1-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2- bromo-4-nitro-N3-(2,2,2-trifluoroethyl)benzene-1,3-diamine (800.00 mg, 1.62 mmol, 1.00 eq.) and B2(OH)4 (436.14 mg, 4.87 mmol, 3.00 eq.) in DMF (6 mL) was added a solution of 4,4-bipyridine (2.53 mg, 0.02 mmol, 0.01 eq.) in DMF (2 mL) dropwise at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The residue was purified by reverse flash chromatography with the following conditions: (column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3) (9:11), to afford title compound (560 mg, 74.53%) as a black solid. LC-MS (ES, m / z): 463.12; 465.12 [M+H]+. Step 4: (E)-N1-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-bromo-4-((4-chloro-5H- 1,2,3-dithiazol-5-ylidene)amino)-N3-(2,2,2-trifluoroethyl)benzene-1,3-diamine

[0250] To a stirred solution of N4-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-3- bromo-N2-(2,2,2-trifluoroethyl)benzene-1,2,4-triamine (385.00 mg, 0.83 mmol, 1.00 eq.) in DMF (5 mL) was added 4,5-dichloro-1,2,3-dithiazol-1-ium (143.79 mg, 0.83 mmol, 1.00 eq.) in portions at room temperature. The resulting mixture was stirred for 30 min at room temperature. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (9:1) to afford title compound (200 mg, 40.19%) as a red solid. LC-MS (ES, m / z): 598.02; 600.02 [M+H]+. Step 5: 6-(((1r,4r)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)amino)-7-bromo-1- (2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-2-carbonitrile and 6-(((1s,4s)-4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)cyclohexyl)amino)-7-bromo-1-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazole-2-carbonitrile

[0251] A solution of (E)-N1-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-bromo-4- ((4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino)-N3-(2,2,2-trifluoroethyl)benzene-1,3-diamine (120 mg, 0.20 mmol, 1.00 eq.) in pyridine (2 mL) was stirred for 4 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mL). The residue was washed with H2O (3x20 mL). The organic layers were concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC with the following conditions: Column, X select CSH C18 OBD Column 30*150mm 5um, n; mobile phase, H2O (0.1% FA) and MeCN; Gradient17% B to 37% B over 8 min to get the trans / cis mixture. The mixture was further separated by Prep-HPLC with the following conditions: Column: XBridge PrepOBD C18, 30*150 mm, 5μm; Mobile Phase A: H2O (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 17% B to 42% B in 9 min. Relative stereochemistry of centers on cyclohexyl ring was assigned based on1H NMR.

[0252] 6-(((1r,4r)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)amino)-7-bromo-1- (2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-2-carbonitrile (4.5 mg, 4.50%) as a off-white solid.LC-MS (ES, m / z): 498.15; 500.15 [M+H]+.1H NMR (300 MHz, Chloroform-d) δ ppm 7.67 (d, J = 9.0 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 5.39 (q, J = 7.8 Hz, 2H), 4.77 (s, 4H), 4.53 (d, J = 7.7 Hz, 1H), 3.40 (s, 4H), 2.29-2.12 (m, 2H), 2.09 (s, 1H), 1.90-1.78 (m, 2H), 1.35- 1.21 (m, 4H).

[0253] 6-(((1s,4s)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)amino)-7-bromo-1- (2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-2-carbonitrile (9.6 mg, 9.59%) as off-white solid.LC-MS (ES, m / z): 498.15; 500.15 [M+H]+.1H NMR (300 MHz, Chloroform-d) δ ppm 7.64 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 9.1 Hz, 1H), 5.39 (q, J = 7.8 Hz, 2H), 4.89 - 4.63 (m, 5H), 3.65-.48 (m, 1H), 3.41-3.29 (m, 3H), 2.10-2.01 (m, 1H), 1.90 -1.60 (m, 5H), 1.55 -1.19 (m, 3H). Compound 1-50Step 1: 2-bromo-4,6-dinitro-N-(2,2,2-trifluoroethyl)aniline

[0254] A solution of 2-bromo-4,6-dinitroaniline (5 g, 19.083 mmol, 1 eq), 2,2,2- trifluoroethyl trifluoromethanesulfonate (11 g, 47.393 mmol, 2.48 eq) and Cs2CO3(15.6 g, 47.879 mmol, 2.51 eq) in DMF (50 mL) was stirred for 30 minutes at 70 °C under nitrogen atmosphere. The resulting solution was quenched by the addition of H2O (500 mL) and extracted with EtOAc (200 mL*3). The combined organic layers were concentrated, and the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in H2O (0.1% TFA), 10% to 56% gradient in 20 min to afford title compound (4 g, 57.88%) as a yellow solid. LC-MS (ES, m / z): 344.04 [M+H]+.Step 2: 6-bromo-N1-(2,2,2-trifluoroethyl)benzene-1,2,4-triamine

[0255] A solution of Fe (2.43 g, 43.513 mmol, 9.98 eq) and NH4Cl (0.93 g, 17.440 mmol, 4 eq) in EtOH (40 mL) and H2O (10 mL) was stirred for 30 minutes at room temperature under nitrogen atmosphere followed by the addition of 2-bromo-4,6-dinitro-N-(2,2,2- trifluoroethyl)aniline (1.5 g, 4.360 mmol, 1 eq) dropwise at room temperature. The resulting mixture was stirred for additional 30 minutes at 80 °C. The resulting solution was concentrated, and the residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (5:1) to afford the title compound (640 mg, 46.51%) as a brown oil. LC-MS (ES, m / z): 284.08 [M+H]+. Step 3: 6-bromo-N4-(1-methylpiperidin-4-yl)-N1-(2,2,2-trifluoroethyl)benzene-1,2,4- triamine

[0256] A solution of 6-bromo-N1-(2,2,2-trifluoroethyl)benzene-1,2,4-triamine (630 mg, 2.218 mmol, 1 eq) and 1-methylpiperidin-4-one (251 mg, 2.218 mmol, 1.00 eq) in DCE (50 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere followed by the addition of STAB (1.41 g, 6.653 mmol, 3.00 eq) dropwise at room temperature. The resulting mixture was stirred for additional 2 hours at room temperature. The reaction was quenched with sat. NaHCO3(aq.) at room temperature. The mixture was extracted with DCM (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (5:1) to afford the title compound (400 mg, 42.58%) as a white solid. LC-MS (ES, m / z): 381.24 [M+H]+. Step 4: 7-bromo-2-(diethoxymethyl)-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazol-5-amine

[0257] A solution of 6-bromo-N1-(2,2,2-trifluoroethyl)benzene-1,2,4-triamine (400 mg, 1.049 mmol, 1 eq) and methyl 2,2-diethoxyacetimidate (338 mg, 2.097 mmol, 2.00 eq) in AcOH was stirred for 30 minutes at room temperature. The mixture was concentrated under reduced pressure and quenched with sat. NaHCO3(aq.) at room temperature. The mixture was extracted with EtOAc (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% NH4HCO3·H2O), 10% to 60% gradient in 20 min to afford title compound (230 mg, 35.55%) as a white oil. LC-MS (ES, m / z): 493.50 [M+H]+. Step 5: 7-bromo-5-((1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazole-2-carbaldehyde

[0258] A solution of 7-bromo-2-(diethoxymethyl)-N-(1-methylpiperidin-4-yl)-1-(2,2,2- trifluoroethyl)-1H-benzo[d]imidazol-5-amine (230 mg, 0.466 mmol, 1 eq) in THF (2 mL), H2O (2 mL) and TFA (0.4 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% TFA), 10% to 55% gradient in 15min to afford title compound (150 mg, 57.56%) as a white oil. LC-MS (ES, m / z): 419.25 [M+H]+. Step 6: (E)-7-bromo-5-((1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazole-2-carbaldehyde oxime

[0259] A solution of 7-bromo-5-((1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)- 1H-benzo[d]imidazole-2-carbaldehyde (140 mg, 0.334 mmol, 1 eq), hydroxylamine (17 mg, 0.515 mmol, 1.54 eq) and Cs2CO3(326 mg, 1.001 mmol, 3.00 eq) in DMF (5 mL) was stirred for 2 hours at 70 °C under nitrogen atmosphere. The resulting mixture was quenched by the addition of H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.1% TFA), 10% to 30% gradient in 10 min to afford title compound (110 mg, 53.10%) as a brown oil. LC-MS (ES, m / z): 434.25 [M+H]+. Step 7: 7-bromo-5-((1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H- benzo[d]imidazole-2-carbonitrile

[0260] A solution of (E)-7-bromo-5-((1-methylpiperidin-4-yl)amino)-1-(2,2,2- trifluoroethyl)-1H-benzo[d]imidazole-2-carbaldehyde oxime (100 mg, 0.230 mmol, 1 eq) and TEA(233 mg, 2.303 mmol, 10.00 eq) in DCE (10 mL) was stirred for 5 minutes at room temperature under nitrogen atmosphere followed by the addition of Tf2O (195 mg, 0.691 mmol, 3.00 eq) dropwise at room temperature. The mixture was stirred for additional 30 minutes at room temperature. The reaction was quenched with sat. NaHCO3(aq.) at room temperature. The mixture was extracted with EtOAc (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: H2O (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 17% B to 42% B in 9 min to afford title compound (10.1 mg, 10.47%) as a yellow solid. LC-MS (ES, m / z): 416.00 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 7.23 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 5.93 (d, J =7.9 Hz, 1H), 5.64-5.50 (m, 2H), 3.29-3.20 (m, 1H), 2.71 (d, J = 12.6 Hz, 2H), 2.17 (s, 3H), 2.10 (t, J = 11.1 Hz, 2H), 1.90 -1.81(m, 2H), 1.47-1.29 (m, 2H).

[0261] Analytical data was obtained for three additional benzimidazole compounds prepared by other methods, as follows: Compound 1-141:1H NMR (400 MHz, CD3OD) δ 8.89 (m, 2H), 8.61 (m, 1H), 7.53 (m, 1H), 5.52 (m, 2H), 4.52 (m, 1H), 4.36 (m, 1H), 3.51 (m, 2H), 3.02(s, 3H), 2.25(m, 2H), 2.2-2.0(m, 2H), 1.9-1.5(m, 4H); Compound 1-142: 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 7.61 (s, 1H), 5.52 (m, 2H), 4.35 (m, 2H), 4.16 (m, 3H), 3.42 (m, 1H), 2.76 (d, 3H), 2.27(s, 3H), 2.25(m, 2H), 2.05(m, 2H), 1.5-2.0 (m, 4H), 1.4 (t, 3H); and Compound 1-144: 1H NMR (400 MHz, CD3OD) δ 8.65 (m, 1H), 7.5-7.43 (m, 2H), 7.16-7.19 (m, 2H), 5.52 (m, 2H), 5.01 (m, 1H), 3.95 (m, 4H), 2.85 (m, 3H), 2.2-2.0 (m, 3H), 1.99-1.69(m, 9H). Example 5. Preparation of Indoles Compound 2-7

[0262] To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonitrile (160 mg, 900.95 umol, 1eq) in DMF (16 mL) were added SEM-Cl (450.62 mg, 2.70 mmol, 478.37 uL, 3 eq) and Cs2CO3(587.10 mg, 1.80 mmol, 2 eq). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated, the residue was diluted with H2O (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~5% EtOAc / petroleum ethergradient @ 100 mL / min) to afford title compound (170 mg, 61.29% yield) as a white solid.Step 2: tert-butyl (1S,5R)-3-[[2-cyano-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2- c]pyridin-6-yl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate

[0263] To a solution of 6-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-2- carbonitrile (20 mg, 64.97 umol, 1eq) in dioxane (0.5 mL) were added tert-butyl (1S,5R)-3- amino-8-azabicyclo[3.2.1]octane-8-carboxylate (19.11 mg, 84.46 umol, 1.3 eq), Cs2CO3(31.75 mg, 97.45 umol, 1.5 eq) and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-2H-imidazole;3- chloropyridine;dichloropalladium (5.16 mg, 6.50 umol, 0.1 eq). The mixture was stirred at 110 °C for 12 hr under N2. The reaction mixture was concentrated, the residue was diluted with H2O (2 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by Prep-TLC (SiO2, petroleum ether / EtOAc=1 / 2) to afford title compound (13 mg, 40.21% yield) as a green oil. Step 3: 6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]amino]-1-(hydroxymethyl)pyrrolo[3,2- c]pyridine-2-carbonitrile

[0264] To a solution of tert-butyl (1S,5R)-3-[[2-cyano-1-(2- trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-yl]amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (10 mg, 20.09 umol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 999.97uL, 672.20 eq), and the reaction mixture was stirred at 25°C for 12 hr under N2. The reaction mixture was concentrated to give crude product (10mg) which was used in the next step. Step 4: 6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]amino]-1H-pyrrolo[3,2-c]pyridine-2- carbonitrile

[0265] To a solution of 6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]amino]-1- (hydroxymethyl)pyrrolo[3,2-c]pyridine-2-carbonitrile (8.27 mg, 20.10 umol, 1 eq, TFA) in MeCN (1 mL) was added K2CO3(27.78mg, 201.03 umol, 10 eq). The mixture was stirred at 20 °C for 0.5 hr. The resultant mixture was filtered, and the filter cake was washed with MeCN (1 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give a crude product (5.37 mg), which was used in next step directly. Step 5: 6-[[(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-1H-pyrrolo[3,2- c]pyridine-2-carbonitrile

[0266] To a solution of 6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]amino]-1H-pyrrolo[3,2- c]pyridine-2-carbonitrile (5.37 mg, 20.09 umol, 1 eq) in MeOH (1 mL) were added AcOH (2.41 mg, 40.18 umol, 2.30 uL, 2 eq) and HCHO (1.30 mg, 16.07 umol, 1.20 uL, 37% purity, 0.8 eq). The mixture was stirred at 20 °C for 1 hr. And then NaBH3CN (6.31 mg, 100.44umol, 5 eq) was added to the reaction mixture and the mixture was stirred at 20 °C for 1 hr. The resulting solution was purified by prep-HPLC neutral condition, column: Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(NH4HCO3)-MeCN]; B%: 5%-35% in 8min to afford title compound (1.1 mg, 18.28% yield) as a white amorphous solid.1H NMR (400 MHz, Chloroform-d) δ ppm 1.88 (br d, J=14.25 Hz, 2 H) 2.00 - 2.06 (m, 2 H) 2.15 - 2.21 (m, 2 H) 2.39 (br dd, J=2.96, 1.43 Hz, 2 H) 2.42 (s, 3 H) 3.22 - 3.31 (m, 2 H) 3.68 - 3.74 (m, 1 H) 5.04 (br d, J=5.92 Hz, 1 H) 6.11 (s, 1 H) 7.12 (s, 1 H) 8.53 (s, 1 H).

[0267] Compounds below were synthesized following the same method: Cm 2-2Compound 2-13 Compound 2-17Step 1: tert-butyl (1S,5R)-3-[[7-bromo-2-cyano-1-(2- trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-yl]amino]-8-azabicyclo[3.2.1]octane-8- carboxylate

[0268] To a solution of tert-butyl (1S,5R)-3-[[2-cyano-1-(2- trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-yl]amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (3.00 mg, 6.03 umol, 1 eq) in MeCN (0.5 mL) was added NBS (2.15 mg, 12.06 umol, 2 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated, the residue was diluted with H2O (1 mL) and extracted with EtOAc (2 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give crude product (3 mg, 86.32% yield) which was used in the next step without purification. Step 2: 6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]amino]-7-bromo-1H-pyrrolo[3,2- c]pyridine-2-carbonitrile

[0269] To a solution of tert-butyl (1S,5R)-3-[[7-bromo-2-cyano-1-(2- trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-yl]amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (3 mg, 5.20 umol, 1 eq) in DCM (0.5 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 1297.93 eq). The mixture was stirred at 20°C for 12 hr. The reaction mixture was concentrated, the residue was purified by prep-HPLC neutral condition, column: Phenomenex Luna 80*30mm*3um; mobile phase: [H2O(TFA)-MeCN]; B%: 1%-30%, 8min to afford title compound (1.7 mg, 94.37% yield, 100.00% purity) as a yellow oil.1H NMR (400 MHz, MeCN-d3) δ ppm 1.27 (s, 1 H) 2.18 (br s, 4 H) 2.35 (br d, J=3.67 Hz, 4 H) 4.06 (br s, 2 H) 4.28 (br d, J=2.57 Hz, 1 H) 5.24 (br d, J=1.34 Hz, 1 H) 7.30 (d, J=1.47 Hz, 1 H) 8.50 (s, 1 H) 9.93 - 10.21 (m, 1 H). Step 3: 7-bromo-6-[[(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-1H- pyrrolo[3,2-c]pyridine-2-carbonitrile

[0270] To a solution of 6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]amino]-7-bromo-1H- pyrrolo[3,2-c]pyridine-2-carbonitrile (27 mg, 58.66 umol, 1 eq, TFA) in MeOH (3 mL) were added HCHO (3.81mg, 46.93 umol, 3.49 uL, 37% purity, 0.8 eq) TEA(8.90 mg, 88.00 umol, 12.25 uL, 1.5 eq) and AcOH (7.05 mg, 117.33 umol, 6.71 uL, 2 eq). The reaction mixture was stirred at 20 °C for 1hr. Then NaBH3CN (18.43 mg, 293.32 umol, 5 eq) was added and the reaction mixture and stirred at 20 °C for 1 hr. The reaction mixture was concentrated, the residue was dissolved was purified by prep-HPLC neutral condition, column: Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(NH4HCO3)-MeCN]; B%: 15%-45%, 8min to afford title compound (7.03 mg, 33.26% yield) as a pale yellow amorphous solid.1H NMR (400 MHz, MeCN-d3) δ ppm 1.72 (br d, J=14.13 Hz, 2 H) 1.90 (br d, J=8.00 Hz, 2 H) 2.02 - 2.13 (m, 5 H) 2.24 (s, 3 H) 3.08 - 3.17 (m, 2 H) 4.23 (q, J=6.88 Hz, 1H) 5.38 (br d, J=6.75 Hz, 1 H) 7.26 (s, 1 H) 8.45 (s, 1 H).

[0271] Compounds below were synthesized following the same method:Compound 2-6Step1: 5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-c]pyridine-2-carbonitrile

[0272] To a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carbonitrile (3.24 g, 14.59 mmol, 1 eq) in DMF (160 mL) was added cesium carbonate (9.51 g, 29.18 mmol, 2 eq) and 2-(chloromethoxy)ethyl-trimethyl-silane (3.65 g, 21.89 mmol, 3.87mL, 1.5 eq).The mixture was stirred at 20 °C for 12 hr. The reaction mixture was concentrated, the residue was diluted with H2O (150 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~5% EtOAc / petroleum ether gradient @ 120 mL / min) to afford title compound (1.38 g, 26.84% yield) as a yellow solid. Step 2: 5-[(1-methyl-4-piperidyl)amino]-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- c]pyridine-2-carbonitrile

[0273] To a solution of 5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-c]pyridine-2- carbonitrile (120 mg, 340.62 umol, 1 eq) in dioxane (3.6 mL) were added 1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-2H-imidazole;3-chloropyridine;dichloropalladium (40.55 mg, 51.09 umol, 0.15 eq), 1-methylpiperidin-4-amine (116.68 mg, 1.02 mmol, 3 eq) and dicesium;carbonate (249.70 mg, 766.39 umol, 2.25 eq) at 20°C.The mixture was stirred at 90°C for 12h under N2. The reaction mixture was concentrated under reduced pressure, the residue was diluted with 10 mL H2O and extracted with EtOAc (10 mL *3). The combined organic phase was dried with anhydrous Na2SO4, the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC neutral condition column: Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(NH4HCO3)- MeCN]; B%: 45%-75%, 8min to afford title compound (450 mg, 68.53% yield) as a yellow gum. Step 3: 4-bromo-5-[(1-methyl-4-piperidyl)amino]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-c]pyridine-2-carbonitrile

[0274] To a solution of 5-[(1-methyl-4-piperidyl)amino]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-c]pyridine-2-carbonitrile (380mg, 985.54 umol, 1 eq) in MeCN (15 mL) were added NBS (175.41 mg, 985.54 umol, 1 eq) at 20°C.The mixture was stirred at 20°C for 2h under N2. The reaction mixture was diluted with 10 mL H2O and extracted with EtOAc (10 mL *3). The combined organic phase was dried with anhydrous Na2SO4, the mixture was filtered, and the filtrate was concentrated under vacuum to provide crude product (450 mg) which was used in the next step without purification. Step 4: 4-bromo-5-[(1-methyl-4-piperidyl)amino]-1H-pyrrolo[2,3-c]pyridine-2-carbonitrile

[0275] To a solution of 4-bromo-5-[(1-methyl-4-piperidyl)amino]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-c]pyridine-2-carbonitrile (450 mg, 968.84 umol, 1 eq) in THF (30 mL) was added TBAF (1 M, 1.45 mL, 1.5 eq) (in THF), and the reaction mixture was stirred at 60°C for 12hr under N2. The reaction mixture was concentrated. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by prep-HPLC TFA condition column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [H2O(TFA)-MeCN]; B%: 5%-40%,8min to afford title compound (15.67 mg, 4.84% yield) as a yellow oil.1H NMR (400 MHz, MeCN-d3) δ ppm 1.79 - 1.91 (m, 2 H) 2.09 - 2.17 (m, 1 H) 2.24 (br d, J=13.68 Hz, 2 H) 2.81 (br d, J=4.02 Hz, 3 H) 2.99 - 3.08 (m, 2 H) 3.16 - 3.36 (m, 1 H) 3.51 (br d, J=12.55 Hz, 1 H) 4.10 - 4.26 (m, 1 H) 6.94 - 7.09 (m, 1 H) 8.47 (s, 1 H) 9.89 (br d, J=2.89 Hz, 1 H) 10.51 - 10.78 (m, 1 H).

[0276] Compounds below were synthesized following the same method:Compound 2-21Step 1: ethyl 5-bromo-3-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0277] A solution of ethyl 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1 g, 3.716 mmol, 1 eq) and Selectfluor (7.90 g, 22.296 mmol, 6 eq) in MeCN (45 mL) and H2O (15 mL) was stirred for overnight at room temperature. The reaction was quenched with brine at room temperature. The resulting mixture was extracted with EtOAc (3 x80 mL). The combined organic layers were washed with brine (3x60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was diluted with H2O (100 mL). The precipitated solids were collected by filtration and washed with H2O (20 mL) to afford title compound (600 mg, 28.12%) as a yellow solid. LCMS: 287.15, 289.15[M+H]+. Step 2: ethyl 5-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- c]pyridine-2-carboxylate

[0278] To a stirred solution of ethyl 5-bromo-3-fluoro-1H-pyrrolo[2,3-c]pyridine-2- carboxylate (400 mg, 1.393 mmol, 1.0 eq) and NaH (50.15 mg, 2.090 mmol, 1.5 eq) in THF (8 mL) was added SEMCl (278.75 mg, 1.672 mmol, 1.2 eq) dropwise at 0°C. The resulting mixture was stirred for additional 1 hour at room temperature. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford title compound (380 mg, 52.28%) as dark green oil. LCMS: 417.20, 419.20 [M+H]+. Step 3: ethyl 3-fluoro-5-((1-methylpiperidin-4-yl)amino)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0279] Under nitrogen atmosphere, a solution of ethyl5-bromo-3-fluoro-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrrolo[2,3-c]pyridine-2-carboxylate (400 mg, 0.958 mmol, 1.0 eq), 1-methylpiperidin-4-amine (218.89 mg, 1.916 mmol, 2 eq), Dppf (52.94 mg, 0.096mmol, 0.1 eq), Dppf Pd G3 (91.45 mg, 0.096 mmol, 0.1 eq) and Cs2CO3(624.55 mg, 1.916 mmol, 2 eq) in dioxane (6 mL) was stirred for 4 hours at 100°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered; the filter cake was washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash, eluted with (MeCN / H2O (10mmol / L NH4HCO3) = 50:50) to afford title compound (300 mg, 55.57%) as a dark green solid. LCMS: [M+H]+451.10. Step 4: 3-fluoro-5-((1-methylpiperidin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0280] A solution of ethyl 3-fluoro-5-[(1-methylpiperidin-4-yl)amino]-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrrolo[2,3-c]pyridine-2-carboxylate (280 mg, 0.621 mmol, 1 eq) in NH3(g) in MeOH (7M,5 mL) was stirred overnight at 50°C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash, eluted with (MeCN / H2O (10mmol / L NH4HCO3) = 58:42) to afford title compound (185 mg, 49.44%) as a yellow solid. LCMS: 422.10 [M+H]+. Step 5: 3-fluoro-5-((1-methylpiperidin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-c]pyridine-2-carbonitrile

[0281] Under nitrogen atmosphere, a solution of 3-fluoro-5-[(1-methylpiperidin-4- yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[2,3-c]pyridine-2-carboxamide (185 mg, 0.439 mmol, 1 eq) in THF (5 mL) was treated with DBU (668.05 mg, 4.390 mmol, 10 eq) for 5 min at -40 °C followed by the addition of PO(OEt)Cl2(357.50 mg, 2.195 mmol, 5 eq) dropwise at -40°C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3aqueous at room temperature. The resulting mixture was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford title compound (140 mg, 79.05%) as a yellow solid. LCMS: 404.00[M+H]+. Step 6: 4-bromo-3-fluoro-5-((1-methylpiperidin-4-yl)amino)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carbonitrile.

[0282] A solution of 3-fluoro-5-[(1-methylpiperidin-4-yl)amino]-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrrolo[2,3-c]pyridine-2-carbonitrile (130 mg, 0.322 mmol, 1 eq) in MeCN (5 mL) was treated for 5 min at room temperature followed by the addition of NBS (40.13 mg, 0.225 mmol, 0.7 eq) dropwise at 0 °C. The resulting mixture was stirred foradditional 30 min at room temperature. The reaction was quenched with saturated Na2SO3aqueous at room temperature. The resulting mixture was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford title compound (110 mg, 70.78%) as a yellow solid. LCMS: 482.05,484.05 [M+H]+. Step 7: 4-bromo-3-fluoro-5-((1-methylpiperidin-4-yl)amino)-1H-pyrrolo[2,3-c]pyridine-2- carbonitrile

[0283] A solution of 4-bromo-3-fluoro-5-[(1-methylpiperidin-4-yl)amino]-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrrolo[2,3-c]pyridine-2-carbonitrile (100 mg, 0.207 mmol, 1 eq) in TFA:DCM =1:5(6 mL) was stirred for 30 min at room temperature. The reaction was quenched with saturated NaHCO3aqueous at room temperature. The resulting mixture was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: H2O (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 14% B to 38% B in 9 min to afford title compound (3.2 mg, 4.19%) as a yellow solid. LC-MS (ES, m / z): 352.10, 354.10 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 8.38 (d, J = 2.2 Hz, 1H), 5.08-4.95 (m, 1H), 3.94-3.86 (m, 1H), 2.99-2.51 (m, 2H), 2.46-2.35 (m, 5H), 1.97-1.82 (m, 2H), 1.66-1.54 (m, 2H). Biological Examples Biological Example 1: Alpha Competition Assay

[0284] The compounds described herein were dispensed into Greiner 784904 microplates in 100 nL of DMSO. Assay buffer was prepared as the following: 50 mM HEPES pH 7.5, 75 mM KCl, 5% glycerol, 0.05% BSA, 0.005% Tween-20. Assay mixture was prepared as the following: 8 nM p53 was incubated with 140 nM of a biotinylated probe based on a high affinity non-covalent ligand in assay buffer for 15 mins.10 uL of assay mixture were then dispensed into wells containing DMSO (high signal control) or compound (test wells). Wells containing all reagents except p53 were utilized as low signal controls. The microplate was then sealed and incubated for 4 hours at room temperature. Detection mixture was prepared as the following: 20 ug / mL of AlphaLISA Ni-NTA acceptor beads and 20 ug / mL AlphaLISA streptavidin donor beads were suspended in assay buffer. Following the 4 hour incubation, the plate seal was removed, and 10 uL of detection mixture was then added to all wells on themicroplate. The plate was then sealed and incubated for 1.5 hours at room temperature. Following the 1.5 hour incubation, the seal was removed and the microplate was then read on a BMG LABTECH PHERAstar FSX plate reader. Plate reader settings were the following: Excitation time = 0.05 sec, integration start = 0.08 sec, integration time = 0.10 sec, gain = 3600, focal height = 12.0 mm.

[0285] The p53 protein construct utilized in this assay was composed of an n-terminal 6xHis tag, p53 residues 94-312, and bearing the following mutations: M133L, V203A, N239Y, N268D, Y220C. Expression and purification were performed with standard methods (Baud MGJ. European Journal of Medicinal Chemistry 2018, Barron L. Journal of Proteomics and Bioinformatics 2018, Krois AS. PNAS, Brandt T. PLoS ONE 2012, Bauer MR. ACS Chemical Biology 2019)

[0286] Data were normalized to high signal (DMSO treated-p53) and low signal (no p53 added) wells. Normalization was performed with the following calculation: % inhibition = (test well - low signal average) / (high signal average - low signal average). IC50values were generated by fitting the normalized data to the following equation: Y=Bottom + (X^Hillslope)*(Top-Bottom) / (X^HillSlope + IC50^HillSlope), where Y = % inhibition previously calculated and X = compound concentration. The data obtained is summarized in Table B-1. For IC50values, ++++ represents < 1µM, +++ represents ≥1 µM and < 5µM, ++ represents ≥ 5 µM and < 100 µM, + represents ≥ 100 µM. Biological Example 2: Fluorescence Resonance Energy Transfer (FRET) Probe Competition Assay Biochemical Assay

[0287] Compounds were dispensed into Greiner 784904 microplates in 100 nL of DMSO. Assay buffer was prepared as the following: 50 mM HEPES pH 7.5, 150 mM NaCl, 0.05% BSA, 0.005% Tween-20, 1 mM TCEP. Assay mixture was prepared as the following: 2 nM avi-p53 was incubated with 35 nM probe (a red-fluorescent probe based on a high affinity non-covalent ligand) in assay buffer for 15 mins.10 uL of assay mixture were then dispensed into wells containing DMSO (high signal control) or compound (test wells). Wells containing all reagents except p53 were utilized as low signal controls. The microplate was then sealed and incubated for 4 hours at room temperature. Following the 4 hour incubation, the seal was removed and the microplate was then read on a BMG LABTECH PHERAstar FSX plate reader. Plate reader settings were the following:

[0288] Integration start: 60 us, Integration time: 400 µs

[0289] The p53 protein construct utilized in this assay was composed of an n-terminal avi- tagged p53 (residues 94-312), and bearing the following mutations: M133L, V203A, N239Y, N268D, Y220C. Biotinylation of the avi-p53 protein was performed in vivo. Expression and purification were performed with standard methods (Baud MGJ. European Journal of Medicinal Chemistry 2018, Barron L. Journal of Proteomics and Bioinformatics 2018, Krois AS. PNAS, Brandt T. PLoS ONE 2012, Bauer MR. ACS Chemical Biology 2019) Biochemical Assay Data Normalization and Analysis

[0290] Data were normalized to high signal (DMSO treated-p53) and low signal (no p53 added) wells. Normalization was performed with the following calculation: % inhibition = (test well - low signal average) / (high signal average - low signal average). IC50values were generated by fitting the normalized data to the following equation: Y=Bottom + (X^Hillslope)*(Top-Bottom) / (X^HillSlope + IC50^HillSlope), where Y = % inhibition previously calculated and X = compound concentration. The results for selected compounds are summarized in Table B-1. For IC50values, ++++ represents < 1µM, +++ represents ≥1 µM and < 5µM, ++ represents ≥ 5 µM and < 100 µM, + represents ≥ 100 µM. Table B-11-88 ++++ 1-90 +++1-132 +++ 1-133 ++++1-179 ++++ ++++ 1-180 ++++ ++++1-223 ++++ 1-224 ++++

Claims

CLAIMS1. A compound of Formula (O)or a salt thereof, wherein:A2is N or CR2; and A3is N or CR3; provided that no more than one of A2and A3is N;X is N or CR5;R ’ is H, D, C1-C3alkyl optionally substituted with one or more independently selected RN1, or C3-C5cycloalkyl optionally substituted with one or more halo;RN1is halo; or cyclopropyl optionally substituted with one or more independently selected halo,R1and R:are independently selected from the group consisting of H. D, and halo, provided that when X is N at least one of R1and R4is halo; one of R2and R3is -N(Ra)-L1-R2a, -N(Ra)-C(O)-R2b, -N(Ra)-C(O)-N(Ra)-R2c, -N(Ra)-R2d, - N(Ra)-M1-N(Ra)-R2e. -N(Ra)-M2-M3-L2-R2f, -N(Ra)-M4-M5-C(O)-XT(Ra)-R28, -N(RS)-M6-M7- O-R2h, -C(O)-N(Ra)-(L3)n-R2i, -N(Ra)-Ms-N(Ra)-L4-R2j. -N(Ra)-M9-N(Ra)-L5-C(O)-R2k, - N(R2l)-C(O)-N(Ra)-L6-R2m, or -N(R5)-M10-R211,R2ais 3- to 14-membered heterocyclyl, 5- to 6-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected. R20;R2bis 3- to 14-membered fully saturated heterocyclyl optionally substituted with one or more independently selected R20;R2cis 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2dis C3-C14cycloalkyl or 3- to 14-membered fully saturated heterocyclyl, each of which is optionally substituted with one or more independently selected R20; R2eis 3- to 14-membered heterocyclyl, C6-C12 aryl, or C3-C14 cycloalkyl, each of which is optionally substituted with one or more independently selected R20; R2f, R2g, R2h, R2i, R2j, R2k, R2l, R2m, and R2n, at each occurrence, are independently 3- to 14- e be ed e e ocycy , C6C a y , 5 o 14- e heteroaryl, or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20; wherein each R20is D, halo; -CN; oxo; -COORa; -N(Ra)2; -ORa; -O-(5- to 12-membered heteroaryl); -SO2Ra; -N(Ra)-C(O)-Ra; -N(Ra)-C(O)-N(Ra)2; -C(O)-N(Ra)2; -C(O)-N(Ra)-R20a; -C(O)-N(Ra)-L7-ORa; C1-C6alkyl optionally substituted with one or more independently selected -ORa, -C(O)ORa, or -SO2Ra; C6-C14aryl optionally substituted with one or more independently selected halo or -ORa; 5- to 14-membered heteroaryl optionally substituted with one or more independently selected halo or C1-C6alkyl; C3-C14cycloalkyl optionally substituted with one or more independently selected -ORaor -SO2Ra; 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected halo; or C2-C6alkynyl optionally substituted with one or more independently selected halo or - N(Ra)C(O)ORa; wherein R20ais C3-C8cycloalkyl optionally substituted with one or more halo; -CN; or ;the other one of R2and R3, if present, is H, D, halo, -NO2, -COORa, -C(O)-N(Ra)2, -N(Ra)- C(O)-Ra, 5- to 14-membered heteroaryl, C1-C6alkyl optionally substituted with one or more independently selected -N(Ra)2or halo, or C3-C6cycloalkyl optionally substituted with one or more independently selected -N(Ra)2or halo; R5, if present, is H, D, halo, C1-C6alkyl optionally substituted with one or more independently selected halo, or C3-C6cycloalkyl optionally substituted with one or more independently selected halo; L1, L2, L3, L4, L5, L6, and L7, at each occurrence, are independently C1-C6alkylene optionally substituted with one or more independently selected -OH, -CN, halogen, or C3-C6cycloalkyl;n is 0 or 1; M1, M2, M3, M4, M5, M6, M7, M8, M9, and M10, at each occurrence, are independently C3-C14cycloalkylene or 3- to 14-membered heterocyclylene, each of which is optionally substituted by one or more substituents independently selected from the group consisting of oxo, -CN, halo, -OH, -OD, C1-C6alkyl, C3-C6cycloalkyl, and -C(O)-N(Ra)2; and wherein Ra, at each occurrence, is independently H; D; C1-C6alkyl optionally substituted with one or more independently selected halogen, -OH, -OD, -O-(C1-C3alkyl), or oxo; or C3-C6cycloalkyl optionally substituted with one or more independently selected halogen, -OH, - OD, -O-(C1-C3alkyl), or oxo.

2. The compound of claim 1, or a salt thereof, wherein RNis H or D.

3. The compound of claim 1, or a salt thereof, wherein RNis C1-C3alkyl optionally substituted with one or more independently selected halo or cyclopropyl; or RNis C3-C5cycloalkyl optionally substituted with one or more halo.

4. The compound of claim 1, or a salt thereof, wherein RNis -CH2CF3, -CH3, -CH2CH3, -C(CH3)HCF3, -CH2CH2F, -CH2CHF2,5. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is: (i) -N(Ra)-L1-R2a, wherein L1is C1-C3alkylene; or (ii) N(Ra)-R2d.

6. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is, ,7. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is: (i) -N(Ra)-M1-N(Ra)-R2e; (ii) -N(Ra)-M8-N(Ra)-L4-R2j, wherein M8is C3-C8cycloalkylene; L4is C1-C3alkylene; and R2jis C6-C12aryl or 5- to 14-membered heteroaryl, each of which is optionally substituted with one or more independently selected R20; or (iii) N(Ra)-M9-N(Ra)- L5-C(O)-R2k, wherein M9is cyclohexylene; L5is C1-C6alkylene; and R2kis 3- to 14- membered heterocyclyl optionally substituted with one or more independently selected R20.

8. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is , ,9. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is (i) -N(Ra)-M2-M3-L2-R2f, wherein R2fis 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R20; M2is cyclohexylene; M3is 5- to 6-membered heterocyclylene; and L2is C1-C3alkylene; (ii) -N(Ra)-M4-M5-C(O)-N(Ra)-R2g, wherein M4 is cyclohexylene; M5is 5- to 8-membered heterocyclylene; and R2gis 3- to 14-membered heterocyclyl or C3-C8cycloalkyl, each of which is optionally substituted with one or more independently selected R20; or (iii) -N(Ra)-M6-M7-O-R2h, wherein M6is cyclohexylene; M7is 4- to 6-membered heterocyclylene; and R2his C6-C12aryl or 5- to 14-membered heteroaryl, each of which is optionally substituted with one or more independently selected R20.

10. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is.

11. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is -N(Ra)-M10-R2n, wherein M10is cyclohexylene; and R2nis 3- to 14-membered heterocyclyl or C3-C14cycloalkyl, each of which is optionally substituted with one or more independently selected R20.

12. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is,13. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is (i) -N(Ra)-C(O)-R2b, and wherein R2bis fully saturated 3- to 8-membered heterocyclyl optionally substituted with one or more independently selected R20; (ii) -N(Ra)-C(O)-N(Ra)-R2c, wherein R2cis 3- to 8-membered heterocyclyl optionally substituted with one or more independently selected R20; or (iii) -C(O)-N(Ra)-R2ior -C(O)-N(Ra)-L3-R2i, wherein R2iis 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected R20.

14. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is -N(R2l)-C(O)-N(Ra)-L6-R2m, wherein R2lis 3- to 14-membered heterocyclyl optionally substituted with one or more independently selected R20and R2mis C6-C12aryl optionally substituted with one or more independently selected R20.

15. The compound of any one of claims 1-4, or a salt thereof, wherein one of R2and R3is16. The compound of any one of claims 1-15, or a salt thereof, wherein the other one of R2and R3, if present, is H or D.

17. The compound of any one of claims 1-16, or a salt thereof, wherein R1and R4are each independently H or D; or one of R1and R4is H or D, and the other of R1and R4is Br or I.

18. The compound of any one of claims 1-16, or a salt thereof, wherein R1is Br and R4is H or D.

19. The compound of any one of claims 1-18, or a salt thereof, wherein R5, if present, is H, D, halo, or C1-C6alkyl optionally substituted with one or more independently selected halo.

20. The compound of any one of claims 1-18, or a salt thereof, wherein R5, if present, is H, F, or CF3.

21. The compound of any one of claims 1-20, or a salt thereof, wherein A2is CR2and A3is CR3.

22. The compound of any one of claims 1-20, or a salt thereof, wherein A2is CR2and A3is N.

23. The compound of any one of claims 1-20, or a salt thereof, wherein A2is N and A3is CR3.

24. The compound of any one of claims 1-23, or a salt thereof, wherein X is N and one of one of R1and R4is halo and the other of R1and R4is H.

25. The compound of any one of claims 1-23, or a salt thereof, wherein X is CR5.

26. A compound, or a salt thereof, selected from the group consisting of the compounds in Table 1 and Table 2 and salts thereof.

27. A pharmaceutical composition comprising a compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

28. A method of modulating the conformation of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of claims 1-26, or the composition of claim 27.

29. A method of restoring wild-type function of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of claims 1-26, or a salt thereof, or the composition of claim 27.

30. A method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-26, or a salt thereof, or the composition of claim 27.

31. The method of claim 30, wherein the proliferative disorder is associated with a mutant p53 protein.

32. The method of claim 31, wherein the mutant p53 protein comprises a Y220C mutation.

33. The method of any one of claims 30-32, wherein the proliferative disorder is cancer.

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