WO2022087624A1 - Composés en tant qu'inhibiteurs de ras et leurs utilisations - Google Patents

Composés en tant qu'inhibiteurs de ras et leurs utilisations Download PDF

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Publication number
WO2022087624A1
WO2022087624A1 PCT/US2021/071978 US2021071978W WO2022087624A1 WO 2022087624 A1 WO2022087624 A1 WO 2022087624A1 US 2021071978 W US2021071978 W US 2021071978W WO 2022087624 A1 WO2022087624 A1 WO 2022087624A1
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alkyl
tetrahydroquinazolin
piperazin
acetonitrile
acryloyl
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PCT/US2021/071978
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English (en)
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Simon Bailey
Frank Kayser
Lawrence R. Mcgee
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Bioardis Llc
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Publication of WO2022087624A1 publication Critical patent/WO2022087624A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • RAS is a family of related proteins that are involved in signal transduction from cell surface receptors to intracellular pathways.
  • KRAS one of the most prevalent isoforms of the Ras subfamily, is a guanosine triphosphatase (GTPase), which alternates between an inactive state that is guanosine diphosphate (GDP)-bound and an active state that is guanosine triphosphate (GTP)-bound. Mutations in KRAS hinder GTPase activity and result in the accumulation of the activated GTP-bound form of KRAS. Subsequently, signaling pathways downstream of KRAS are overstimulated, leading to cell growth and division, and ultimately to tumor formation. [0004] Mutations in RAS genes constitute the most commonly mutated gene family in cancers.
  • mutations in KRAS gene are detected in 84% of all RAS-mutant cancers and in 25-30% of all tumors.
  • G12C glycine-12 to cysteine
  • MYH-associated polyposis familial colon cancer syndrome.
  • Mutations in the KRAS gene has been detected in several types of cancer, including but not limited to, lung cancer, colorectal cancer, pancreatic cancer, gall bladder cancer, thyroid cancer, and bile duct cancer.
  • a composition comprising the compound of formula (I’), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method of treating a disease mediated by KRAS in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of formula (I’), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I’), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.
  • the disease is cancer.
  • a method of inhibiting KRAS in a cell comprising contacting the cell with a therapeutically effective amount of the compound of formula (I’), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I’), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.
  • a compound of formula (I): or a pharmaceutically acceptable salt thereof wherein R A , R B , X, R 1 , R 2 , and R 3 are as described herein.
  • a composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method of treating a disease mediated by KRAS in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.
  • the disease is cancer.
  • a method of inhibiting KRAS in a cell comprising contacting the cell with a therapeutically effective amount of the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.
  • a therapeutically effective amount of the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.
  • KRAS G12C refers to a mutant form of a mammalian KRAS protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
  • KRAS G12C inhibitor refers to compounds of the present disclosure that are described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRAS G12C.
  • KRAS G12C-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRAS G12C mutation.
  • a non-limiting example of a KRAS G12C-associated disease or disorder is a KRAS G12C-associated cancer.
  • Alkyl 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., C 1-10 means one to ten carbon atoms).
  • Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1-20 alkyl”), having 1 to 10 carbon atoms (a “C 1-10 alkyl”), having 6 to 10 carbon atoms (a “C 6-10 alkyl”), having 1 to 6 carbon atoms (a “C 1-6 alkyl”), having 2 to 6 carbon atoms (a “C 2-6 alkyl”), or having 1 to 4 carbon atoms (a “C 1-4 alkyl”).
  • 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.
  • 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 “C 1 -C 20 alkylene”), having 1 to 10 carbon atoms (a “C 1 -C 10 alkylene”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkylene”), having 1 to 6 carbon atoms (a “C 1 -C 6 alkylene”), 1 to 5 carbon atoms (a “C 1 -C 5 alkylene”), 1 to 4 carbon atoms (a “C 1 -C 4 alkylene”) or 1 to 3 carbon atoms (a “C 1 -C 3 alkylene”).
  • alkylene examples include, but are not limited to, groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH 2 CH(CH 3 )-), butylene (-CH 2 (CH 2 ) 2 CH 2 -), isobutylene (-CH 2 CH(CH 3 )CH 2 -), pentylene (-CH 2 (CH 2 ) 3 CH 2 -), hexylene (-CH 2 (CH 2 ) 4 CH 2 -), heptylene (-CH 2 (CH 2 ) 5 CH 2 -), octylene (-CH 2 (CH 2 ) 6 CH 2 -), and the like.
  • groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH 2 CH(CH 3 )-), butylene (-CH 2 (
  • Alkoxy refers to an –O-alkyl. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • 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 “C 2-20 alkenyl”), having 6 to 10 carbon atoms (a “C 6-10 alkenyl”), having 2 to 8 carbon atoms (a “C 2-8 alkenyl”), having 2 to 6 carbon atoms (a “C 2-6 alkenyl”), or having 2 to 4 carbon atoms (a “C 2-4 alkenyl”).
  • alkenyl group examples 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, and the like.
  • 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,
  • Cycloalkyl refers to and includes, unless otherwise stated, cyclic univalent nonaromatic hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (i.e., C 3-10 means 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 12 annular carbon atoms.
  • a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C 3-8 cycloalkyl”), having 3 to 6 carbon atoms (a “C 3-6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a “C 3-4 cycloalkyl”).
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
  • a cycloalkyl group may be fused with aryl, heteroaryl, or heterocyclyl.
  • a cycloalkyl group having more than one ring where at least one ring is aryl, heteroaryl, or heterocyclyl is connected to the parent structure at an annular atom in the nonaromatic hydrocarbon cyclic group.
  • “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.
  • An aryl comprising more than one ring may be fused, bridged or spiro, or any combination thereof.
  • 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.
  • 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.
  • Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C 6-14 aryl”).
  • An aryl group may be fused with heteroaryl, cycloalkyl, or heterocyclyl.
  • an aryl group having more than one ring where at least one ring is heteroaryl, cycloalkyl, or heterocyclyl is connected to the parent structure at an annular atom in the aromatic carbocyclic group.
  • “Heteroaryl” as used herein refers to an unsaturated 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) which condensed rings may or may not be aromatic.
  • a heteroaryl comprising more than one ring may be fused, bridged or spiro, or any combination thereof.
  • one or more of the rings can be cycloalkyl, aryl or heterocyclyl.
  • a heteroaryl 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.
  • a heteroaryl 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 heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • 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 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • 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.
  • 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.
  • a heteroaryl group may be fused with aryl, cycloalkyl, or heterocyclyl.
  • a heteroaryl group having more than one ring where at least one ring is aryl, cycloalkyl, or heterocyclyl is connected to the parent structure at an annular atom in the aromatic cyclic group having at least one annular heteroatom.
  • a heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, 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.
  • one or more of the rings can be cycloalkyl or aryl, but not heteroaryl.
  • a heterocyclic group having more than one ring where at least one ring is aryl may be connected to the parent structure at either an aryl ring position or at a non-aromatic ring position.
  • a heterocyclic group having more than one ring where at least one ring is aryl is connected to the parent structure at a non-aromatic ring position.
  • a heterocyclic group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • the heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
  • 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.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7- membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 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.
  • 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.
  • a heterocyclyl group may be fused with aryl, cycloalkyl, or heteroaryl.
  • a heterocyclyl group having more than one ring where at least one ring is aryl, cycloalkyl, or heteroaryl is connected to the parent structure at an annular atom in the non- aromatic cyclic group having at least one heteroatom.
  • “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.
  • a haloalkyl is an alkyl group that is substituted with one or more halogens.
  • 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.
  • alkyl-OH refers to an alkyl substituted by one or more hydroxyl groups.
  • alkyl-OH is meant to include alkyl substituted by one hydroxyl group, as well as alkyl substituted by multiple hydroxyl groups.
  • alkyl-OH includes -CH 2 OH, -CH(OH)CH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, and the like.
  • alkyl-CN refers to an alkyl substituted by one or more cyano groups.
  • alkyl-CN is meant to include alkyl substituted by one cyano group, as well as alkyl substituted by multiple cyano groups.
  • alkyl-CN includes -CH 2 CN, -CH 2 CH 2 CN, -CH(CN)CH 3 , and the like.
  • Amino refers to the group -NH 2 .
  • Cyano refers to the group -C ⁇ N.
  • Hydroxy or “hydroxyl” refers to the group -OH.
  • 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 of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • 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.
  • an optionally substituted group is unsubstituted.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • a wavy line that intersects a bond in a chemical structure indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.
  • “individual,” “subject,” and “patient,” use interchangeably, as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent.
  • the individual is a human. In some embodiments, the individual has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the individual has been identified or diagnosed as having a cancer having a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the individual has a tumor that is positive for a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit). In some embodiments, the individual is suspected of having a KRAS G12C gene-associated cancer.
  • a regulatory agency-approved e.g., FDA-approved, assay or kit
  • the individual has a tumor that is positive for a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit). In some embodiments, the individual is suspected of having a KRAS G12C gene-associated cancer.
  • the individual has a clinical record indicating that the individual has a tumor that has a KRAS G12C mutation (and optionally the clinical record indicates that the individual should be treated with any of the compositions provided herein).
  • regulatory agency is a country's agency for the approval of the medical use of pharmaceutical agents with the country.
  • a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
  • FDA U.S. Food and Drug Administration
  • 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.
  • the methods of the present disclosure contemplate any one or more of these aspects of treatment.
  • an effective amount intends such amount of a compound described herein which should be effective in a given therapeutic form.
  • 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.
  • a “therapeutically effective amount” refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome.
  • 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.
  • 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 preferably 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.
  • “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 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 of the present disclosure 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.
  • 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 of the present disclosure as an active ingredient.
  • 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.
  • prodrug refers to a compound which provides an active compound following administration to the individual in which it is used, by a chemical and/or biological process in vivo (e.g., by hydrolysis and/or an enzymatic conversion).
  • the prodrug itself may be active, or it may be relatively inactive, then transformed into a more active compound.
  • This disclosure embraces prodrugs of the compounds described herein.
  • R A and R B are independently H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), -C(O)O(C 1 -C 6 alkyl), -C(O)(C 2 -C 6 alkenyl), or C 6 -C 10 aryl, wherein C 1 -C 6 alkylene is optionally substituted by 1-6 groups independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and halo; or R A and R B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroary
  • a compound of formula (I): or a stereoisomer or pharmaceutically acceptable salt thereof wherein: R A and R B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl optionally contain 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 —
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl optionally contain 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), - C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl),
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10- membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl), -NH-S(O)(C 1 - C 6 alkyl), -NH-S(O) 2 (C 1 -C 6 alkyl), -N(C
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 9- to 10-membered heterocyclyl optionally containing 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 9- to 10-membered heterocyclyl is optionally substituted by 1 group selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, C 1 -C 3 alkyl-CN, -O-(C 1 -C 3 alkyl), -C(O)O(C 1 -C 3 alkyl), -NH- C(O)(C 1 -C 3 alkyl), -NH-S(O)(C 1 -C 3 alkyl), -NH-S(O) 2 (C 1 -C 3 alkyl), -N(C 1 -C
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 9- to 10-membered heterocyclyl optionally containing 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 9- to 10-membered heterocyclyl is unsubstituted.
  • the 9- to 10-membered heterocyclyl contains 1 nitrogen atom.
  • the 9- to 10-membered heterocyclyl contains 2 nitrogen atoms.
  • the 9- to 10-membered heterocyclyl contains 1 nitrogen atom and 1 oxygen atom.
  • the 9- to 10-membered heterocyclyl contains 1 nitrogen atom and 1 sulfur atom.
  • the 9- to 10-membered heterocyclyl is a fused ring system, wherein a 5- to 6-membered monocyclic heterocyclyl is fused to a phenyl ring and the point of attachment to the remainder of the molecule (i.e., the 5,6,7,8-tetrahydroquinazoline) is through the 5- to 6-membered monocyclic heterocyclic ring.
  • the 9- to 10- membered heterocyclyl is indolinyl, isoindolinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,2,3,4- tetrahydroquinolinyl, or 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, the 9- to 10- membered heterocyclyl is 2,3-dihydrobenzo[1,4]oxazinyl.
  • R A and R B are taken together with the nitrogen atom to which they are attached to form indolinyl, isoindolinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,2,3,4-tetrahydroquinolinyl, or 1,2,3,4- tetrahydroisoquinolinyl, each of which is optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, - O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl), and -NH-S(O) 2 (C 1 -C 6 alkyl).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form indolinyl, isoindolinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 2,3-dihydrobenzo[1,4]oxazinyl, each of which is optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl), and -NH-S(O) 2 (C 1 -C 6 alkyl).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form indolinyl, isoindolinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,2,3,4-tetrahydroquinolinyl, or 1,2,3,4- tetrahydroisoquinolinyl, each of which is optionally substituted by 1 group selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -O-(C 1 -C 3 alkyl), - C(O)O(C 1 -C 3 alkyl), -NH-C(O)(C 1 -C 3 alkyl), and -NH-S(O) 2 (C 1 -C 3 alkyl).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form indolinyl, isoindolinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 2,3-dihydrobenzo[1,4]oxazinyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -O-(C 1 -C 3 alkyl), -C(O)O(C 1 -C 3 alkyl), -NH-C(O)(C 1 - C 3 alkyl), and -NH-S(O) 2 (C 1 -C 3 alkyl).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form indolinyl, isoindolinyl, 2,3-dihydro-1H- benzo[d]imidazolyl, 1,2,3,4-tetrahydroquinolinyl, or 1,2,3,4-tetrahydroisoquinolinyl, each of which is optionally substituted by 1 group selected from the group consisting of hydroxy, F, Cl, Br, cyano, oxo, -CH 3 , -CF 3 , -O-CH 3 , -C(O)OCH 3 , -NH-C(O)-CH 3 , and -NH-S(O) 2 -CH 3 .
  • R A and R B are taken together with the nitrogen atom to which they are attached to form indolinyl, isoindolinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 2,3-dihydrobenzo[1,4]oxazinyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of hydroxy, F, Cl, Br, cyano, oxo, -CH 3 , -CF 3 , -O-CH 3 , -C(O)OCH 3 , -NH-C(O)-CH 3 , and -NH-S(O) 2 -CH 3 .
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 5- to 10-membered heteroaryl optionally containing 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 5- to 10- membered heteroaryl is optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl), -NH-S(O)(C 1 - C 6 alkyl), -NH-S(O) 2 (C 1 -C 6 alkyl), -N(C 1-5 groups independently selected from the group consisting
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 9-membered heteroaryl optionally containing 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 9-membered heteroaryl is optionally substituted by 1 group selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, C 1 -C 3 alkyl-CN, -O-(C 1 -C 3 alkyl), -C(O)O(C 1 -C 3 alkyl), -NH-C(O)(C 1 -C 3 alkyl), -NH-S(O)(C 1 - C 3 alkyl), -NH-S(O) 2 (C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)C
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 9-membered heteroaryl optionally containing 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 9-membered heteroaryl is unsubstituted.
  • the 9- membered heteroaryl contains 1 nitrogen atom.
  • the 9-membered heteroaryl contains 2 nitrogen atoms.
  • the 9-membered heteroaryl contains 1 nitrogen atom and 1 oxygen atom.
  • the 9-membered heteroaryl contains 1 nitrogen atom and 1 sulfur atom.
  • the 9-membered heteroaryl is a fused ring system, wherein a 5- to 6-membered monocyclic heteroaryl is fused to a phenyl ring and the point of attachment to the remainder of the molecule (i.e., the 5,6,7,8-tetrahydroquinazoline) is through the 5- to 6-membered monocyclic heteroaryl ring.
  • the 9- membered heteroaryl is 1H-indolyl.
  • R A and R B are taken together with the nitrogen atom to which they are attached to form 1H-indolyl, which is optionally substituted by 1-5 groups independently selected from the group consisting of C 1 -C 6 alkyl and -O-(C 1 -C 6 alkyl). In some embodiments, R A and R B are taken together with the nitrogen atom to which they are attached to form 1H-indolyl, which is optionally substituted by 1 group selected from the group consisting of C 1 -C 3 alkyl and -O-(C 1 -C 3 alkyl).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form 1H-indolyl, which is optionally substituted by 1 group selected from the group consisting of -CH 3 and -O-CH 3 .
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl optionally contain 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1-5 groups independently selected from the group consisting of
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 9- to 10-membered heterocyclyl or 9- to 10-membered heteroaryl, wherein the 9- to 10-membered heterocyclyl and 9- to 10-membered heteroaryl optionally contain 1 additional nitrogen atom, and wherein the 9- to 10-membered heterocyclyl and 9- to 10-membered heteroaryl are optionally substituted by 1-2 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, - O-(C 1 -C 3 alkyl), -C(O)O(C 1 -C 3 alkyl), -NH-C(O)(C 1 -C 3 alkyl), and -NH-S(O) 2 (C 1 -C 3 alkyl).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 9- to 10-membered heterocyclyl or 9- to 10-membered heteroaryl, wherein the 9- to 10-membered heterocyclyl and 9- to 10-membered heteroaryl optionally contain 1 additional nitrogen atom, and wherein the 9- to 10-membered heterocyclyl and 9- to 10- membered heteroaryl are optionally substituted by 1-2 groups independently selected from the group consisting of hydroxy, F, Cl, Br, cyano, oxo, -CH 3 , -CF 3 , -O-CH 3 , -C(O)OCH 3 , -NH- C(O)-CH 3 , and -NH-S(O) 2 -CH 3 .
  • R A and R B are taken together with the nitrogen atom to which they are attached to form each of which is optionally substituted by -OH, Br, CN, oxo, -CH 3 , -CF 3 , -OCH 3 , -C(O)-OCH 3 , -NH-C(O)-CH 3 , or -NH-S(O) 2 -CH 3 , wherein the wavy line denotes attachment to the 5,6,7,8-tetrahydroquinazoline of formula (I).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form each of which is optionally substituted by 1-3 groups independently selected from the group consisting of -OH, F, Cl, Br, CN, oxo, -CH 3 , -CF 3 , - OCH 3 , -C(O)-OCH 3 , -NH-C(O)-CH 3 , and -NH-S(O) 2 -CH 3 , wherein the wavy line denotes attachment to the 5,6,7,8-tetrahydroquinazoline of formula (I) or formula (I’).
  • R A and R B are taken together with the nitrogen atom to which they are attached to form
  • R A and R B are taken together with the nitrogen atom to which they are attached to form , wherein the wavy line denotes attachment to the 5,6,7,8- tetrahydroquinazoline of formula (I) or formula (I’).
  • X is -NR a R b , -O-(C 1 -C 6 alkylene)-NH 2 , -O-(C 1 -C 6 alkylene)- NH(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), -O-(C 1 -C 6 alkylene)-(4- to 10-membered heterocyclyl), -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), -O-(C 1 -C 6 alkylene)-(5- to 10-membered heteroaryl), -O-(C 1 -C 6 alkyl), -O-(C 3 -C 6 cycloalky
  • X is -NR a R b , -O-(C 1 -C 3 alkylene)-NH 2 , -O-(C 1 -C 3 alkylene)- NH(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), -O-(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), -O-(C 1 -C 6 alkylene)-(phenyl), -O-(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), -O-(C 1 -C 3 alkyl), -O-(C 3 -C 6 cycloalkyl), -O-O-(C 1 -C
  • X is -NR a R b .
  • X is -NR a R b , wherein R a and R b are independently H, C 1 -C 6 alkyl, -C(O)(C 2 -C 6 alkenyl), -C(O)O(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -(C 1 -C 6 alkylene)-C(O)-(4- to 10-membered heterocyclyl), -(C 1 -C 6 alkylene)-C(O)-NH 2 , -(C 1 -C 6 alkylene)-C(O)-NH-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-C(O)-N(C 1 -
  • X is -NR a R b , wherein R a and R b are independently H, C 1 -C 6 alkyl, -C(O)(C 2 -C 6 alkenyl), - C(O)O(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 4- to 10-membered heterocyclyl, 5- to 10- membered heteroaryl, -(C 1 -C 6 alkylene)-C(O)-(4- to 10-membered heterocyclyl), -(C 1 -C 6 alkylene)-C(O)-NH 2 , -(C 1 -C 6 alkylene)-C(O)-NH-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-C(O)-N(C 1 - C 6 alkyl)(C 1 -C 6 alkyl), -(C 1 -C 6
  • R a groups as specified below can be combined with any R b groups as specified below.
  • X is -NR a R b , wherein R a is H, and R b is -CH 3 .
  • X is - NR a R b , wherein R a and R b are both -CH 3 .
  • X is -NR a R b , wherein R a is H, C 1 -C 6 alkyl, -C(O)(C 2 -C 6 alkenyl), -C(O)O(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -(C 1 -C 6 alkylene)-C(O)-(4- to 10-membered heterocyclyl), -(C 1 - C 6 alkylene)-C(O)-NH 2 , -(C 1 -C 6 alkylene)-C(O)-NH-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-C(O)- N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-
  • X is -NR a R b , wherein R a is H.
  • X is -NR a R b , wherein R a is C 1 -C 6 alkyl. In some embodiments, R a is C 1 -C 3 alkyl. In some embodiments, R a is methyl, ethyl, n-propyl, or isopropyl.
  • X is -NR a R b , wherein R a is -C(O)(C 2 -C 6 alkenyl). In some embodiments, R a is -C(O)(C 2 -C 4 alkenyl).
  • R a is -C(O)OCH 3 , - C(O)OCH 2 CH 3 , -C(O)OCH 2 CH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , or -C(O)OC(CH 3 ) 3 .
  • X is -NR a R b , wherein R a is C 3 -C 6 cycloalkyl, wherein the C 3 - C 6 cycloalkyl is optionally substituted by 1-5 R x groups. In some embodiment, R a is C 3 -C 6 cycloalkyl optionally substituted by 1-3 R x groups.
  • R a is C 3 -C 6 cycloalkyl optionally substituted by 1 R x group. In some embodiment, R a is unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, R a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1-3 R x groups. [0072] In some embodiments, X is -NR a R b , wherein R a is C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted by 1-5 R x groups.
  • R a is C 6 -C 10 aryl optionally substituted by 1-3 R x groups. In some embodiments, R a is C 6 -C 10 aryl optionally substituted by 1 R x group. In some embodiments, R a is unsubstituted C 6 -C 10 aryl. In some embodiments, R a is phenyl or naphthyl, each of which is optionally substituted by 1-3 R x groups.
  • X is -NR a R b , wherein R a is 4- to 10-membered heterocyclyl, wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • R a is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1- 3 R x groups.
  • R a is 4- to 6-membered heterocyclyl, wherein the 4- to 6- membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • R a is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • the 4- to 6- membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl. In some embodiment, R a is piperidinyl optionally substituted by 1 R x group.
  • X is -NR a R b , wherein R a is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups.
  • R a is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-3 R x groups.
  • R a is 5- to 6-membered heteroaryl, wherein the 5- to 6- membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1 R x group.
  • R a is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted.
  • the 5- to 6- membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 5- to 6-membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of O and N.
  • the 5- to 6-membered heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 2 nitrogen atoms.
  • the 5- to 6-membered heteroaryl contains 1 sulfur atom and 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 3 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimindinyl, pyrazinyl, or triazinyl.
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-C(O)-(4- to 10- membered heterocyclyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • R a is -(C 1 -C 3 alkylene)-C(O)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • R a is -(C 1 - C 3 alkylene)-C(O)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • R a is -(C 1 -C 3 alkylene)-C(O)-(4- to 6- membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • R a is -CH 2 -C(O)-(4- to 6-membered heterocyclyl), -CH 2 CH 2 -C(O)-(4- to 6-membered heterocyclyl), or -CH 2 CH 2 CH 2 -C(O)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl.
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-C(O)-NH 2 . In some embodiments, R a is -(C 1 -C 3 alkylene)-C(O)-NH 2 . In some embodiments, R a is -CH 2 -C(O)- NH 2 , -CH 2 CH 2 -C(O)-NH 2 , or -CH 2 CH 2 CH 2 -C(O)-NH 2 .
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-C(O)-NH-(C 1 - C 6 alkyl). In some embodiments, R a is -(C 1 -C 3 alkylene)-C(O)-NH-(C 1 -C 3 alkyl). In some embodiments, R a is -CH 2 -C(O)-NH-CH 3 , -CH 2 -C(O)-NH-CH 2 CH 3 , -CH 2 -C(O)-NH- CH 2 CH 2 CH 3 , or -CH 2 -C(O)-NH-CH(CH 3 ) 2 .
  • R a is -CH 2 CH 2 -C(O)-NH- CH 3 , -CH 2 CH 2 -C(O)-NH-CH 2 CH 3 , -CH 2 CH 2 -C(O)-NH-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -C(O)-NH- CH(CH 3 ) 2 .
  • R a is -CH 2 CH 2 CH 2 -C(O)-NH-CH 3 , -CH 2 CH 2 CH 2 -C(O)-NH- CH 2 CH 3 , -CH 2 CH 2 CH 2 -C(O)-NH-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -C(O)-NH-CH(CH 3 ) 2 .
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
  • R a is -(C 1 -C 3 alkylene)-C(O)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl). In some embodiments, R a is -CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 -C(O)-N(CH 3 )-CH 2 CH 3 , -CH 2 - C(O)-N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -C(O)-N(CH 3 )-CH(CH 3 ) 2 , -CH 2 -C(O)-N(CH 2 CH 3 ) 2 , -CH 2 - C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -C(O)-N(CH 2 CH 3 ) 2 , -CH 2 - C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -
  • R a is -CH 2 CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 CH 2 -C(O)-N(CH 3 )-CH 2 CH 3 , -CH 2 CH 2 - C(O)-N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -C(O)-N(CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 -C(O)-N(CH 2 CH 3 ) 2 , - CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 - C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 - C(O)-N(CH 2 CH 2 CH 3 ) 2 , -CH
  • R a is -CH 2 CH 2 CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)- N(CH 3 )-CH 2 CH 3 , -CH 2 CH 2 CH 2 -C(O)-N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 -C(O)-N(CH 3 )- CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O
  • R a is -CH 2 CH 2 CH 2 -C(O)-N(CH 3 ) 2 .
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-NH 2 .
  • R a is -(C 1 -C 3 alkylene)-NH 2 .
  • R a is -CH 2 -NH 2 , -CH 2 CH 2 - NH 2 , or -CH 2 CH 2 CH 2 -NH 2 .
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-NH-(C 1 -C 6 alkyl). In some embodiments, R a is -(C 1 -C 3 alkylene)-NH-(C 1 -C 3 alkyl). In some embodiments, R a is -CH 2 -NH-CH 3 , -CH 2 -NH-CH 2 CH 3 , -CH 2 -NH-CH 2 CH 2 CH 3 , or -CH 2 -NH-CH(CH 3 ) 2 .
  • R a is -CH 2 CH 2 -NH-CH 3 , -CH 2 CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 -NH- CH 2 CH 2 CH 3 , or -CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • R a is -CH 2 CH 2 CH 2 -NH-CH 3 , -CH 2 CH 2 CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 CH 2 -NH-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R a is -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • R a is -CH 2 -N(CH 3 ) 2 , -CH 2 -N(CH 3 )-CH 2 CH 3 , -CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 -N(CH 2 CH 3 ) 2 , -CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 - N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -CH 2 - N(CH(CH 3 ) 2 ) 2 .
  • R a is -CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 CH 2 -N(CH 3 )-CH 2 CH 3 , - CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 3 ) 2 , -CH 2 CH 2 - N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , - CH 2 CH 2 -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -CH 2 CH 2 -N(CH(CH 3 ) 2 ) 2 .
  • R a is - CH 2 CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 3 )-CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 )- CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-5 R x groups.
  • R a is -(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-3 R x groups.
  • R a is -(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1 R x group. In some embodiments, R a is -(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl unsubstituted.
  • R a is -CH 2 -(C 3 -C 6 cycloalkyl), -CH 2 CH 2 -(C 3 -C 6 cycloalkyl), or -CH 2 CH 2 CH 2 -(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-3 R x groups.
  • R a is -CH 2 -(cyclopropyl), -CH 2 - (cyclobutyl), -CH 2 -(cyclopentyl), or -CH 2 -(cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • R a is -CH 2 CH 2 -(cyclopropyl), -CH 2 CH 2 -(cyclobutyl), -CH 2 CH 2 -(cyclopentyl), or -CH 2 CH 2 - (cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • R a is -CH 2 CH 2 CH 2 -(cyclopropyl), - CH 2 CH 2 CH 2 -(cyclobutyl), -CH 2 CH 2 CH 2 -(cyclopentyl), or -CH 2 CH 2 CH 2 -(cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-(4- to 10- membered heterocyclyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • R a is -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • R a is -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • R a is -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • R a is -CH 2 -(4- to 6- membered heterocyclyl), -CH 2 CH 2 -(4- to 6-membered heterocyclyl), or -CH 2 CH 2 CH 2 -(4- to 6- membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O.
  • the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl.
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-5 R x groups.
  • R a is - (C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-3 R x groups. In some embodiments, R a is -(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1 R x group. In some embodiments, R a is -(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is unsubstituted.
  • R a is -CH 2 -(C 6 -C 10 aryl), - CH 2 CH 2 -(C 6 -C 10 aryl), or -CH 2 CH 2 CH 2 -(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-3 R x groups.
  • R a is -CH 2 -(phenyl) or -CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • R a is -CH 2 CH 2 -(phenyl) or -CH 2 CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups. In some embodiments, R a is -CH 2 CH 2 CH 2 -(phenyl) or -CH 2 CH 2 CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • X is -NR a R b , wherein R a is -(C 1 -C 6 alkylene)-(5- to 10- membered heteroaryl), wherein the 5- to 10-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups.
  • R a is -(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-3 R x groups.
  • R a is -(C 1 -C 3 alkylene)- (5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1 R x group.
  • R a is -(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted.
  • R a is -CH 2 -(5- to 6-membered heteroaryl), -CH 2 CH 2 -(5- to 6-membered heteroaryl), or -CH 2 CH 2 CH 2 -(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 5- to 6-membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of O and N.
  • the 5- to 6- membered heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 2 nitrogen atoms.
  • the 5- to 6-membered heteroaryl contains 3 nitrogen atoms.
  • the 5- to 6-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimindinyl, pyrazinyl, or triazinyl.
  • X is -NR a R b , wherein R b is H, C 1 -C 6 alkyl, -C(O)(C 2 -C 6 alkenyl), -C(O)O(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -(C 1 -C 6 alkylene)-C(O)-(4- to 10-membered heterocyclyl), -(C 1 - C 6 alkylene)-C(O)-NH 2 , -(C 1 -C 6 alkylene)-C(O)-NH-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-C(O)- N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-
  • X is -NR a R b , wherein R b is H.
  • X is -NR a R b , wherein R b is C 1 -C 6 alkyl. In some embodiments, R b is C 1 -C 3 alkyl. In some embodiments, R b is methyl, ethyl, n-propyl, or isopropyl.
  • X is -NR a R b , wherein R b is -C(O)(C 2 -C 6 alkenyl). In some embodiments, R b is -C(O)(C 2 -C 4 alkenyl).
  • R b is -C(O)OCH 3 , - C(O)OCH 2 CH 3 , -C(O)OCH 2 CH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , or -C(O)OC(CH 3 ) 3 .
  • X is -NR a R b , wherein R b is C 3 -C 6 cycloalkyl, wherein the C 3 - C 6 cycloalkyl is optionally substituted by 1-5 R x groups. In some embodiment, R b is C 3 -C 6 cycloalkyl optionally substituted by 1-3 R x groups.
  • R b is C 3 -C 6 cycloalkyl optionally substituted by 1 R x group. In some embodiment, R b is unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, R b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1-3 R x groups. [0092] In some embodiments, X is -NR a R b , wherein R b is C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted by 1-5 R x groups.
  • R b is C 6 -C 10 aryl optionally substituted by 1-3 R x groups. In some embodiments, R b is C 6 -C 10 aryl optionally substituted by 1 R x group. In some embodiments, R b is unsubstituted C 6 -C 10 aryl. In some embodiments, R b is phenyl or naphthyl, each of which is optionally substituted by 1-3 R x groups.
  • X is -NR a R b , wherein R b is 4- to 10-membered heterocyclyl, wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • R b is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1- 3 R x groups.
  • R b is 4- to 6-membered heterocyclyl, wherein the 4- to 6- membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • R b is 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • the 4- to 6- membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl. In some embodiment, R b is piperidinyl optionally substituted by 1 R x group.
  • X is -NR a R b , wherein R b is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups.
  • R b is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-3 R x groups.
  • R b is 5- to 6-membered heteroaryl, wherein the 5- to 6- membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1 R x group.
  • R b is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted.
  • the 5- to 6- membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 5- to 6-membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of O and N.
  • the 5- to 6-membered heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 2 nitrogen atoms.
  • the 5- to 6-membered heteroaryl contains 3 nitrogen atoms.
  • the 5- to 6-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimindinyl, pyrazinyl, or triazinyl.
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-C(O)-(4- to 10- membered heterocyclyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • R b is -(C 1 -C 3 alkylene)-C(O)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • R b is -(C 1 - C 3 alkylene)-C(O)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • R b is -(C 1 -C 3 alkylene)-C(O)-(4- to 6- membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • R b is -CH 2 -C(O)-(4- to 6-membered heterocyclyl), -CH 2 CH 2 -C(O)-(4- to 6-membered heterocyclyl), or -CH 2 CH 2 CH 2 -C(O)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl.
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-C(O)-NH 2 . In some embodiments, R b is -(C 1 -C 3 alkylene)-C(O)-NH 2 . In some embodiments, R b is -CH 2 -C(O)- NH 2 , -CH 2 CH 2 -C(O)-NH 2 , or -CH 2 CH 2 CH 2 -C(O)-NH 2 .
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-C(O)-NH-(C 1 - C 6 alkyl). In some embodiments, R b is -(C 1 -C 3 alkylene)-C(O)-NH-(C 1 -C 3 alkyl). In some embodiments, R b is -CH 2 -C(O)-NH-CH 3 , -CH 2 -C(O)-NH-CH 2 CH 3 , -CH 2 -C(O)-NH- CH 2 CH 2 CH 3 , or -CH 2 -C(O)-NH-CH(CH 3 ) 2 .
  • R b is -CH 2 CH 2 -C(O)-NH- CH 3 , -CH 2 CH 2 -C(O)-NH-CH 2 CH 3 , -CH 2 CH 2 -C(O)-NH-CH 2 CH 2 CH 3 , or -CH 2 CH 2 -C(O)-NH- CH(CH 3 ) 2 .
  • R b is -CH 2 CH 2 CH 2 -C(O)-NH-CH 3 , -CH 2 CH 2 CH 2 -C(O)-NH- CH 2 CH 3 , -CH 2 CH 2 CH 2 -C(O)-NH-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -C(O)-NH-CH(CH 3 ) 2 .
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
  • R b is -(C 1 -C 3 alkylene)-C(O)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl). In some embodiments, R b is -CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 -C(O)-N(CH 3 )-CH 2 CH 3 , -CH 2 - C(O)-N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -C(O)-N(CH 3 )-CH(CH 3 ) 2 , -CH 2 -C(O)-N(CH 2 CH 3 ) 2 , -CH 2 - C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -C(O)-N(CH 2 CH 3 ) 2 , -CH 2 - C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -
  • R b is -CH 2 CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 CH 2 -C(O)-N(CH 3 )-CH 2 CH 3 , -CH 2 CH 2 - C(O)-N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -C(O)-N(CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 -C(O)-N(CH 2 CH 3 ) 2 , - CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 - C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 - C(O)-N(CH 2 CH 2 CH 3 ) 2 , -CH
  • R b is -CH 2 CH 2 CH 2 -C(O)-N(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)- N(CH 3 )-CH 2 CH 3 , -CH 2 CH 2 CH 2 -C(O)-N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 -C(O)-N(CH 3 )- CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O)-N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -C(O
  • R b is -CH 2 CH 2 CH 2 -C(O)-N(CH 3 ) 2 .
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-NH 2 .
  • R b is -(C 1 -C 3 alkylene)-NH 2 .
  • R b is -CH 2 -NH 2 , -CH 2 CH 2 - NH 2 , or -CH 2 CH 2 CH 2 -NH 2 .
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-NH-(C 1 -C 6 alkyl). In some embodiments, R b is -(C 1 -C 3 alkylene)-NH-(C 1 -C 3 alkyl). In some embodiments, R b is -CH 2 -NH-CH 3 , -CH 2 -NH-CH 2 CH 3 , -CH 2 -NH-CH 2 CH 2 CH 3 , or -CH 2 -NH-CH(CH 3 ) 2 .
  • R b is -CH 2 CH 2 -NH-CH 3 , -CH 2 CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 -NH- CH 2 CH 2 CH 3 , or -CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • R b is -CH 2 CH 2 CH 2 -NH-CH 3 , -CH 2 CH 2 CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 CH 2 -NH-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R b is -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • R b is -CH 2 -N(CH 3 ) 2 , -CH 2 -N(CH 3 )-CH 2 CH 3 , -CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 -N(CH 2 CH 3 ) 2 , -CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 - N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -CH 2 - N(CH(CH 3 ) 2 ) 2 .
  • R b is -CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 CH 2 -N(CH 3 )-CH 2 CH 3 , - CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 3 ) 2 , -CH 2 CH 2 - N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , - CH 2 CH 2 -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -CH 2 CH 2 -N(CH(CH 3 ) 2 ) 2 .
  • R b is - CH 2 CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 3 )-CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 )- CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-5 R x groups.
  • R b is -(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-3 R x groups.
  • R b is -(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1 R x group. In some embodiments, R b is -(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl unsubstituted.
  • R b is -CH 2 -(C 3 -C 6 cycloalkyl), -CH 2 CH 2 -(C 3 -C 6 cycloalkyl), or -CH 2 CH 2 CH 2 -(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-3 R x groups.
  • R b is -CH 2 -(cyclopropyl), -CH 2 - (cyclobutyl), -CH 2 -(cyclopentyl), or -CH 2 -(cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • R b is -CH 2 CH 2 -(cyclopropyl), -CH 2 CH 2 -(cyclobutyl), -CH 2 CH 2 -(cyclopentyl), or -CH 2 CH 2 - (cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • R b is -CH 2 CH 2 CH 2 -(cyclopropyl), - CH 2 CH 2 CH 2 -(cyclobutyl), -CH 2 CH 2 CH 2 -(cyclopentyl), or -CH 2 CH 2 CH 2 -(cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-(4- to 10- membered heterocyclyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • R b is -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • R b is -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • R b is -(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • R b is -CH 2 -(4- to 6- membered heterocyclyl), -CH 2 CH 2 -(4- to 6-membered heterocyclyl), or -CH 2 CH 2 CH 2 -(4- to 6- membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O.
  • the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl.
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-5 R x groups.
  • R b is - (C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-3 R x groups. In some embodiments, R b is -(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1 R x group. In some embodiments, R b is -(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is unsubstituted.
  • R b is -CH 2 -(C 6 -C 10 aryl), - CH 2 CH 2 -(C 6 -C 10 aryl), or -CH 2 CH 2 CH 2 -(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-3 R x groups.
  • R b is -CH 2 -(phenyl) or -CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • R b is -CH 2 CH 2 -(phenyl) or -CH 2 CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups. In some embodiments, R b is -CH 2 CH 2 CH 2 -(phenyl) or -CH 2 CH 2 CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • X is -NR a R b , wherein R b is -(C 1 -C 6 alkylene)-(5- to 10- membered heteroaryl), wherein the 5- to 10-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups.
  • R b is -(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-3 R x groups.
  • R b is -(C 1 -C 3 alkylene)- (5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1 R x group.
  • R b is -(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted.
  • R b is -CH 2 -(5- to 6-membered heteroaryl), -CH 2 CH 2 -(5- to 6-membered heteroaryl), or -CH 2 CH 2 CH 2 -(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 5- to 6-membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of O and N.
  • the 5- to 6- membered heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 2 nitrogen atoms.
  • the 5- to 6-membered heteroaryl contains 3 nitrogen atoms.
  • the 5- to 6-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimindinyl, pyrazinyl, or triazinyl.
  • X is -NR a R b , wherein R a is H or -C(O)(C 2 -C 6 alkenyl), and R b is -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl) or 4- to 10-membered heterocyclyl, wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • X is -NR a R b , wherein R a is H, and R b is -(C 1 -C 6 alkylene)- C(O)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl) or 4- to 10-membered heterocyclyl, wherein the 4- to 10- membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • X is -NR a R b , wherein R a is H, and R b is -CH 2 CH 2 CH 2 -C(O)-N(CH 3 ) 2 or 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O and is optionally substituted by 1-2 R x groups.
  • X is -NR a R b , wherein R a is -C(O)(C 2 -C 6 alkenyl), and R b is 4- to 10-membered heterocyclyl, wherein the 4- to 10- membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • each R x is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), or -C(O)O(C 1 -C 6 alkyl).
  • each R x is independently C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), or -C(O)O(C 1 -C 4 alkyl). In some embodiments, each R x is independently -CH 3 , - CH 2 CH 2 F, -CH 2 CH 2 -O-CH 3 , or -C(O)O(t-butyl).
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-5 R x groups.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1-3 R x groups.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1 R x group.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 6-membered heterocyclyl is unsubstituted.
  • the 4- to 6-membered heterocyclyl contains 1 nitrogen atom.
  • the 4- to 6-membered heterocyclyl contains 2 nitrogen atoms.
  • the 4- to 6-membered heterocyclyl contains 1 nitrogen atom and 1 oxygen atom.
  • the 4- to 6-membered heterocyclyl contains 1 nitrogen atom and 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, imidazolidinyl, mopholinyl, or thiomorpholinyl. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, or piperazinyl.
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-5 R x groups.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 6- membered heterocyclyl is optionally substituted by 1-3 R x groups.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10- membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1 R x group.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing two additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is unsubstituted.
  • the 4- to 10-membered heterocyclyl contains 2 nitrogen atoms.
  • the 4- to 10- membered heterocyclyl contains 1 nitrogen atom and 1 oxygen atom.
  • the 4- to 10-membered heterocyclyl contains 1 nitrogen atom and 1 sulfur atom.
  • the 4- to 10-membered heterocyclyl contains 3 nitrogen atoms.
  • the 4- to 10-membered heterocyclyl contains 2 nitrogen atoms and 1 oxygen atom. In some embodiments, the 4- to 10-membered heterocyclyl contains 2 nitrogen atoms and 1 sulfur atom. In some embodiments, the 4- to 10-membered heterocyclyl contains 1 nitrogen atom and 2 oxygen atoms. In some embodiments, the 4- to 10-membered heterocyclyl contains 1 nitrogen atom and 2 sulfur atoms. In some embodiments, the 4- to 10-membered heterocyclyl contains 1 nitrogen atom, 1 oxygen atom, and 1 sulfur atom.
  • the 4- to 10- membered heterocyclyl is a 7- to 10-membered heterocyclyl, wherein the 7- to 10-membered heterocyclyl is a fused or spiro heterocylic ring and is optionally substituted with R x (e.g., R x is C 1 -C 3 alkyl).
  • R x is C 1 -C 3 alkyl.
  • the 4- to 10-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, imidazolidinyl, mopholinyl, or thiomorpholinyl.
  • the 4- to 10-membered heterocyclyl is azetidinyl, pyrrolidinyl, or piperazinyl.
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is optionally substituted 1-2 R x groups.
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is substituted by 1-2 groups selected from C 1 -C 6 alkyl, -O-(C 1 -C 6 alkyl), -NH 2 , -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), oxo, or 4- to 10-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl.
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is substituted by 1-2 groups selected from halo, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), - (C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -NH 2 , -NH-(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)(C 1 -C 6 haloalkyl), -N(C 1 -C 6
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is substituted by 1-2 groups selected from - CH 3 , -O-CH 3 , -NH 2 , -N(CH 3 ) 2 , -C(O)N(CH 3 ) 2 , oxo, unsubstituted morpholinyl, and piperazinyl substituted by -CH 3 .
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is substituted by 1-2 groups selected from F, -CH 3 , -CH 2 -O-CH 3 , -CH 2 -O- CH(CH 3 ) 2 , -O-CH 3 , -CH 2 -N(CH 3 ) 2 , -NH 2 , -N(H)-CH 3 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )- CH 2 CHF 2 , -N(CH 3 )-CH 2 CF 3 , -N(CH 3 )-CH 2 CH 2 -O-CH 3 , -C(O)N(CH 3 ) 2 , oxo, un
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl substituted by -O-CH 3 , -N(CH 3 ) 2 , unsubstituted morpholinyl, or piperazinyl substituted by -CH 3 .
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl substituted by 1-2 groups selected from -CH 3 , -CH 2 -O-CH 3 , -CH 2 -O-CH(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , -O-CH 3 , -N(H)-CH 3 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH 2 CHF 2 , -N(CH 3 )-CH 2 CF 3 , - N(CH 3 )-CH 2 CH 2 -O-CH 3 , unsubstituted azetidinyl, unsubstituted morpholinyl, and piperazinyl substituted by -CH 3 .
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form pyrrolidinyl substituted by -NH 2 , - N(CH 3 ) 2 , or -C(O)N(CH 3 ) 2 .
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form pyrrolidinyl substituted by 1- 2 groups selected from F, -O-CH 3 , -NH 2 , -N(H)-CH 3 , -N(CH 3 ) 2 , and -C(O)N(CH 3 ) 2 .
  • X is -NR a R b , wherein R a and R b are taken together with the nitrogen atom to which they are attached to form piperazinyl substituted by oxo and -CH 3 .
  • X is -O-(C 1 -C 6 alkylene)-NH 2 . In some embodiments, X is - O-(C 1 -C 3 alkylene)-NH 2 . In some embodiments, X is -O-CH 2 -NH 2 . In some embodiments, X is - O-CH 2 CH 2 -NH 2 . In some embodiments, X is -O-CH 2 CH 2 CH 2 -NH 2 . [0111] In some embodiments, X is -O-(C 1 -C 6 alkylene)-NH(C 1 -C 6 alkyl).
  • X is -O-(C 1 -C 3 alkylene)-NH(C 1 -C 3 alkyl). In some embodiments, X is -O-CH 2 - NH-CH 3 , -O-CH 2 -NH-CH 2 CH 3 , -O-CH 2 -NH-CH 2 CH 2 CH 3 , or -O-CH 2 -NH-CH(CH 3 ) 2 .
  • X is -O-CH 2 CH 2 -NH-CH 3 , -O-CH 2 CH 2 -NH-CH 2 CH 3 , -O-CH 2 CH 2 -NH- CH 2 CH 2 CH 3 , or -O-CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • X is -O-CH 2 CH 2 CH 2 -NH- CH 3 , -O-CH 2 CH 2 CH 2 -NH-CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -NH-CH 2 CH 2 CH 3 , or -O-CH 2 CH 2 CH 2 -NH- CH(CH 3 ) 2 .
  • X is -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, X is -O-(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • X is -O-CH 2 -N(CH 3 ) 2 , -O-CH 2 -N(CH 3 )-CH 2 CH 3 , -O-CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , - O-CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 - N(CH 2 CH 3 )-CH(CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -O- CH 2 -N(CH(CH 3 ) 2 ) 2 .
  • X is -O-CH 2 CH 2 -N(CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 3 )- CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -O-CH 2 CH 2 - N(CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , -O- CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(CH
  • X is -O-CH 2 CH 2 CH 2 -N(CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 3 )- CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -O- CH 2 CH 2 CH 2 -N(CH 2 CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 CH 2 - N(CH 2 CH 3 )-CH(CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 )- CH(CH 3 ) 2 , or -O-CH 2
  • X is -O-CH 2 CH 2 - N(CH 3 ) 2 .
  • X is -O-(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 - C 6 cycloalkyl is optionally substituted by 1-5 R x groups.
  • X is -O-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-3 R x groups.
  • X is -O-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1 R x group. In some embodiments, X is -O-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl unsubstituted.
  • X is -O-CH 2 -(C 3 -C 6 cycloalkyl), -O-CH 2 CH 2 -(C 3 -C 6 cycloalkyl), or -O-CH 2 CH 2 CH 2 -(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 -(cyclopropyl), -O-CH 2 -(cyclobutyl), -O-CH 2 -(cyclopentyl), or -O- CH 2 -(cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 CH 2 -(cyclopropyl), - O-CH 2 CH 2 -(cyclobutyl), -O-CH 2 CH 2 -(cyclopentyl), or -O-CH 2 CH 2 -(cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 CH 2 CH 2 -(cyclopropyl), -O-CH 2 CH 2 CH 2 -(cyclobutyl), -O- CH 2 CH 2 CH 2 -(cyclopentyl), or -O-CH 2 CH 2 CH 2 -(cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • X is -O-(C 1 -C 6 alkylene)-(4- to 10-membered heterocyclyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-5 R x groups.
  • X is -O-(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • X is -O-(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • X is -O-(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • X is -O-CH 2 -(4- to 6-membered heterocyclyl), -O-CH 2 CH 2 -(4- to 6-membered heterocyclyl), or -O-CH 2 CH 2 CH 2 -(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6- membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6- membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 4- to 6- membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl.
  • X is -O- CH 2 -(pyrrolidinyl), -O-CH 2 CH 2 -(pyrrolidinyl), -O-CH 2 -(morpholinyl), or -O-CH 2 CH 2 - (morpholinyl), wherein the pyrrolidinyl and morpholinyl are optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 -(azetidinyl), -O-CH 2 -(pyrrolidinyl), -O-CH 2 CH 2 - (pyrrolidinyl), -O-CH 2 -(morpholinyl), or -O-CH 2 CH 2 -(morpholinyl), wherein the azetidinyl, pyrrolidinyl, and morpholinyl are optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 -(pyrrolidinyl) or -O-CH 2 CH 2 -(pyrrolidinyl), wherein the pyrrolidinyl is optionally substituted by 1 R x group.
  • X is -O-CH 2 -(azetidinyl), -O-CH 2 - (pyrrolidinyl), or -O-CH 2 CH 2 -(pyrrolidinyl), wherein the azetidinyl and pyrrolidinyl is optionally substituted by 1 R x group.
  • X is -O-CH 2 CH 2 -(morpholinyl), wherein the morpholinyl is unsubstituted.
  • X is -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-5 R x groups.
  • X is -O-(C 1 -C 3 alkylene)- (C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-3 R x groups.
  • X is -O-(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1 R x group. In some embodiments, X is -O-(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is unsubstituted.
  • X is -O-CH 2 -(C 6 -C 10 aryl), -O- CH 2 CH 2 -(C 6 -C 10 aryl), or -O-CH 2 CH 2 CH 2 -(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 -(phenyl) or -O-CH 2 - (naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 CH 2 -(phenyl) or -O-CH 2 CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • X is -O- CH 2 CH 2 CH 2 -(phenyl) or -O-CH 2 CH 2 CH 2 -(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • X is -O-CH 2 -(phenyl), wherein the phenyl is substituted by 1 R x group.
  • X is -O-CH 2 -(phenyl), wherein the phenyl is unsubstituted.
  • X is -O-(C 1 -C 6 alkylene)-(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups.
  • X is -O-(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-3 R x groups.
  • X is -O-(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1 R x group.
  • X is -O-(C 1 -C 3 alkylene)-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted.
  • X is -O-CH 2 -(5- to 6-membered heteroaryl), -O- CH 2 CH 2 -(5- to 6-membered heteroaryl), or -O-CH 2 CH 2 CH 2 -(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups.
  • the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 5- to 6-membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of O and N.
  • the 5- to 6-membered heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 2 nitrogen atoms.
  • the 5- to 6-membered heteroaryl contains 3 nitrogen atoms.
  • the 5- to 6-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimindinyl, pyrazinyl, or triazinyl.
  • X is -O-(C 1 -C 6 alkyl). In some embodiments, X is -O-(C 1 -C 3 alkyl).
  • X is -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • X is -O-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-5 R x groups.
  • X is -O-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1-3 R x groups.
  • X is -O-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted by 1 R x group. In some embodiments, X is -O-(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl unsubstituted.
  • X is -O-(cyclopropyl), -O-(cyclobutyl), -O-(cyclopentyl), or -O- (cyclohexyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted by 1-3 R x groups.
  • X is -O-(4- to 10-membered heterocyclyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups.
  • X is -O-(4- to 6- membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1-3 R x groups. In some embodiments, X is -O-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 2 R x groups.
  • X is -O-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by 1 R x group.
  • X is -O-(4- to 6-membered heterocyclyl), wherein the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S and is unsubstituted.
  • the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl.
  • X is -O-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-5 R x groups. In some embodiments, X is -O-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1-3 R x groups. In some embodiments, X is -O-(C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is optionally substituted by 1 R x group. In some embodiments, X is -O- (C 6 -C 10 aryl), wherein the C 6 -C 10 aryl is unsubstituted.
  • X is -O-(phenyl) or -O-(naphthyl), wherein the phenyl and naphthyl are optionally substituted by 1-3 R x groups.
  • X is -O-(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups.
  • X is -O-(5- to 6- membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-3 R x groups. In some embodiments, X is -O-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1 R x group.
  • X is -O-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted.
  • the 5- to 6- membered heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 5- to 6-membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of O and N.
  • the 5- to 6-membered heteroaryl contains 1-3 nitrogen atoms.
  • the 5- to 6-membered heteroaryl contains 1 nitrogen atom.
  • the 5- to 6-membered heteroaryl contains 1 oxygen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl contains 1 oxygen atom and 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 1 sulfur atom and 2 nitrogen atoms. In some embodiments, the 5- to 6-membered heteroaryl contains 3 nitrogen atoms.
  • the 5- to 6-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimindinyl, pyrazinyl, or triazinyl.
  • each R x is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-NH 2 , -(C 1 -C 6 alkylene)-NH-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-NH-C(O)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)-C(O)-O-(C 1 -C 6 alkyl), -NH 2 , -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)(O)-O-
  • each R x is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, - (C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-NH 2 , -(C 1 -C 6 alkylene)-NH-(C 1 -C 6 alkyl), - (C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-NH-C(O)-O-(C 1 -C 6 alkyl), -(C 1 - C 6 alkylene)-N(C 1 -C 6 alkyl)-C(O)-O-(C 1 -C 6 alkyl), -NH 2 , -NH-(C 1 -C 6 alkyl), -N(C 1 -C 6 alky
  • R x is halo. In some embodiments, R x is F, Cl, or Br. [0125] In some embodiments, R x is C 1 -C 6 alkyl. In some embodiments, R x is C 1 -C 3 alkyl. In some embodiments, R x is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R x is methyl, ethyl, or isopropyl. In some embodiments, R x is -CH 3 . [0126] In some embodiments, R x is C 1 -C 6 haloalkyl.
  • R x is C 1 -C 6 haloalkyl containing 1-13 halogen atoms. In some embodiments, R x is C 1 -C 3 haloalkyl. In some embodiments, R x is C 1 -C 3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R x is C 1 -C 2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of fluoro, chloro, and bromo atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of fluoro and chloro atoms.
  • the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of fluoro and chloro atoms.
  • R x is -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 , -CH 2 Cl, or -CHFCl. In some embodiments, R x is -CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH 2 CH 2 Br, or -CH 2 CH 2 I.
  • R x is -CH 2 CH 2 F. In some embodiments, R x is -CH 2 CHF 2 or -CH 2 CF 3 . [0127] In some embodiments, R x is -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl). In some embodiments, R x is -(C 1 -C 3 alkylene)-O-(C 1 -C 6 alkyl). In some embodiments, R x is -(C 1 -C 6 alkylene)-O-(C 1 -C 3 alkyl). In some embodiments, R x is -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl).
  • R x is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O- CH(CH 3 ) 2 . In some embodiments, R x is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O- CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R x is -CH 2 CH 2 CH 2 -O-CH 3 , - CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R x is -CH 2 CH 2 -O-CH 3 .
  • R x is -(C 1 -C 6 alkylene)-NH 2 .
  • R x is - (C 1 -C 3 alkylene)-NH 2 .
  • R x is -CH 2 -NH 2 .
  • R x is - CH 2 CH 2 -NH 2 . In some embodiments, R x is -CH 2 CH 2 CH 2 -NH 2 . [0129] In some embodiments, R x is -(C 1 -C 6 alkylene)-NH-(C 1 -C 6 alkyl). In some embodiments, R x is -(C 1 -C 3 alkylene)-NH-(C 1 -C 3 alkyl). In some embodiments, R x is -CH 2 -NH- CH 3 , -CH 2 -NH-CH 2 CH 3 , -CH 2 -NH-CH 2 CH 2 CH 3 , or -CH 2 -NH-CH(CH 3 ) 2 .
  • R x is -CH 2 CH 2 -NH-CH 3 , -CH 2 CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 -NH-CH 2 CH 2 CH 3 , or - CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • R x is -CH 2 CH 2 CH 2 -NH-CH 3 , -CH 2 CH 2 CH 2 - NH-CH 2 CH 3 , -CH 2 CH 2 CH 2 -NH-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • R x is -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R x is -(C 1 -C 3 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R x is - (C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • R x is -CH 2 -N(CH 3 ) 2 , -CH 2 - N(CH 3 )-CH 2 CH 3 , -CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 -N(CH 2 CH 3 ) 2 , - CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , -CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 - N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -CH 2 -N(CH(CH 3 ) 2 ) 2 .
  • R x is -CH 2 CH 2 - N(CH 3 ) 2 , -CH 2 CH 2 -N(CH 3 )-CH 2 CH 3 , -CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -N(CH 3 )- CH(CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 -N(CH 2 CH 3 )- CH(CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -CH 2 CH 2 - N(CH(CH 3 ) 2 ) 2 .
  • R x is -CH 2 CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 3 )- CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 - N(CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , - CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 -N(
  • R x is -(C 1 -C 6 alkylene)-NH-C(O)-O-(C 1 -C 6 alkyl). In some embodiments, R x is -(C 1 -C 3 alkylene)-NH-C(O)-O-(C 1 -C 4 alkyl).
  • R x is - CH 2 -NH-C(O)-O-CH 3 , -CH 2 -NH-C(O)-O-CH 2 CH 3 , -CH 2 -NH-C(O)-O-CH 2 CH 2 CH 3 , -CH 2 -NH- C(O)-O-CH(CH 3 ) 2 , or -CH 2 -NH-C(O)-O-C(CH 3 ) 3 .
  • R x is -CH 2 CH 2 -NH- C(O)-O-CH 3 , -CH 2 CH 2 -NH-C(O)-O-CH 2 CH 3 , -CH 2 CH 2 -NH-C(O)-O-CH 2 CH 2 CH 3 , -CH 2 CH 2 - NH-C(O)-O-CH(CH 3 ) 2 , or -CH 2 CH 2 -NH-C(O)-O-C(CH 3 ) 3 .
  • R x is - CH 2 CH 2 CH 2 -NH-C(O)-O-CH 3 , -CH 2 CH 2 CH 2 -NH-C(O)-O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -NH-C(O)- O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -NH-C(O)-O-CH(CH 3 ) 2 , or -CH 2 CH 2 CH 2 -NH-C(O)-O- C(CH 3 ) 3 .
  • R x is -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)-C(O)-O-(C 1 -C 6 alkyl). In some embodiments, R x is -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)-C(O)-O-(C 1 -C 4 alkyl).
  • R x is -CH 2 -N(CH 3 )-C(O)-O-CH 3 , -CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 3 , -CH 2 -N(CH 3 )- C(O)-O-CH 2 CH 2 CH 3 , -CH 2 -N(CH 3 )-C(O)-O-CH(CH 3 ) 2 , or -CH 2 -N(CH 3 )-C(O)-O-C(CH 3 ) 3 .
  • R x is -CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 3 , -CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 3 , - CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 2 CH 3 , -CH 2 CH 2 -N(CH 3 )-C(O)-O-CH(CH 3 ) 2 , or -CH 2 CH 2 - N(CH 3 )-C(O)-O-C(CH 3 ) 3 .
  • R x is -CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 3 , - CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH(CH 3 ) 2 , or -CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-C(CH 3 ) 3 .
  • R x is -NH 2 .
  • R x is -NH-(C 1 -C 6 alkyl). In some embodiments, R x is -NH- (C 1 -C 3 alkyl). In some embodiments, R x is -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH 2 CH 2 CH 3 , or -NH- CH(CH 3 ) 2 . [0135] In some embodiments, R x is -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R x is -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • R x is -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , - N(CH 3 )-CH 2 CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , - N(CH 2 CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 .
  • R x is -N(CH 3 ) 2 .
  • R x is -N(C 1 -C 6 alkyl)(C 1 -C 6 haloalkyl).
  • R x is -N(C 1 -C 3 alkyl)(C 1 -C 3 haloalkyl).
  • the C 1 -C 3 haloalkyl contains 1-7 halogen atoms.
  • R x is -N(C 1 -C 3 alkyl)(C 1 -C 2 haloalkyl).
  • the C 1 -C 2 haloalkyl contains 1-5 halogen atoms.
  • the halogen atoms are independently selected from the group consisting of fluoro, chloro, and bromo atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of fluoro and chloro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of fluoro and chloro atoms.
  • R x is - N(CH 3 )-CH 2 F, -N(CH 3 )-CHF 2 , -N(CH 3 )-CF 3 , -N(CH 3 )-CH 2 Cl, -N(CH 3 )-CHCl 2 , -N(CH 3 )-CCl 3 , -N(CH 3 )-CF 2 Cl, -N(CH 3 )-CFCl 2 , or -N(CH 3 )-CHFCl.
  • R x is -N(CH 3 )- CH 2 -CH 2 F, -N(CH 3 )-CH 2 -CHF 2 , -N(CH 3 )-CH 2 -CF 3 , -N(CH 3 )-CH 2 -CH 2 Cl, -N(CH 3 )-CH 2 - CHCl 2 , -N(CH 3 )-CH 2 -CCl 3 , -N(CH 3 )-CH 2 -CF 2 Cl, -N(CH 3 )-CH 2 -CFCl 2 , or -N(CH 3 )-CH 2 - CHFCl.
  • R x is -N(CH 2 CH 3 )-CH 2 F, -N(CH 2 CH 3 )-CHF 2 , -N(CH 2 CH 3 )-CF 3 , -N(CH 2 CH 3 )-CH 2 Cl, -N(CH 2 CH 3 )-CHCl 2 , -N(CH 2 CH 3 )-CCl 3 , -N(CH 2 CH 3 )-CF 2 Cl, - N(CH 2 CH 3 )-CFCl 2 , or -N(CH 2 CH 3 )-CHFCl.
  • R x is -N(CH 2 CH 3 )-CH 2 - CH 2 F, -N(CH 2 CH 3 )-CH 2 -CHF 2 , -N(CH 2 CH 3 )-CH 2 -CF 3 , -N(CH 2 CH 3 )-CH 2 -CH 2 Cl, -N(CH 2 CH 3 )- CH 2 -CHCl 2 , -N(CH 2 CH 3 )-CH 2 -CCl 3 , -N(CH 2 CH 3 )-CH 2 -CF 2 Cl, -N(CH 2 CH 3 )-CH 2 -CFCl 2 , or - N(CH 2 CH 3 )-CH 2 -CHFCl.
  • R x is -N(CH 2 CH 2 CH 3 )-CH 2 F, - N(CH 2 CH 2 CH 3 )-CHF 2 , -N(CH 2 CH 2 CH 3 )-CF 3 , -N(CH 2 CH 2 CH 3 )-CH 2 Cl, -N(CH 2 CH 2 CH 3 )- CHCl 2 , -N(CH 2 CH 2 CH 3 )-CCl 3 , -N(CH 2 CH 2 CH 3 )-CF 2 Cl, -N(CH 2 CH 2 CH 3 )-CFCl 2 , or - N(CH 2 CH 2 CH 3 )-CHFCl.
  • R x is -N(CH 2 CH 2 CH 3 )-CH 2 -CH 2 F, - N(CH 2 CH 2 CH 3 )-CH 2 -CHF 2 , -N(CH 2 CH 2 CH 3 )-CH 2 -CF 3 , -N(CH 2 CH 2 CH 3 )-CH 2 -CH 2 Cl, - N(CH 2 CH 2 CH 3 )-CH 2 -CHCl 2 , -N(CH 2 CH 2 CH 3 )-CH 2 -CCl 3 , -N(CH 2 CH 2 CH 3 )-CH 2 -CF 2 Cl, - N(CH 2 CH 2 CH 3 )-CH 2 -CFCl 2 , or -N(CH 2 CH 2 CH 3 )-CH 2 -CHFCl.
  • R x is - N(CH(CH 3 ) 2 )-CH 2 F, -N(CH(CH 3 ) 2 )-CHF 2 , -N(CH(CH 3 ) 2 )-CF 3 , -N(CH(CH 3 ) 2 )-CH 2 Cl, - N(CH(CH 3 ) 2 )-CHCl 2 , -N(CH(CH 3 ) 2 )-CCl 3 , -N(CH(CH 3 ) 2 )-CF 2 Cl, -N(CH(CH 3 ) 2 )-CFCl 2 , or - N(CH(CH 3 ) 2 )-CHFCl.
  • R x is -N(CH(CH 3 ) 2 )-CH 2 -CH 2 F, -N(CH(CH 3 ) 2 )- CH 2 -CHF 2 , -N(CH(CH 3 ) 2 )-CH 2 -CF 3 , -N(CH(CH 3 ) 2 )-CH 2 -CH 2 Cl, -N(CH(CH 3 ) 2 )-CH 2 -CHCl 2 , - N(CH(CH 3 ) 2 )-CH 2 -CCl 3 , -N(CH(CH 3 ) 2 )-CH 2 -CF 2 Cl, -N(CH(CH 3 ) 2 )-CH 2 -CFCl 2 , or - N(CH(CH 3 ) 2 )-CH 2 -CHFCl.
  • R x is -N(CH 3 )-CH 2 -CHF 2 . In some embodiments, R x is -N(CH 3 )-CH 2 -CF 3 . [0137] In some embodiments, R x is -N(C 1 -C 6 alkyl)[(C 1 -C 6 alkylene)-O-( C 1 -C 6 alkyl)]. In some embodiments, R x is -N(C 1 -C 3 alkyl)[(C 1 -C 3 alkylene)-O-( C 1 -C 3 alkyl)].
  • R x is -N(CH 3 )-CH 2 -O-CH 3 , -N(CH 3 )-CH 2 -O-CH 2 -CH 3 , -N(CH 3 )-CH 2 -O-CH 2 - CH 2 -CH 3 , -N(CH 3 )-CH 2 -O-CH(CH 3 ) 2 , -N(CH 3 )-CH 2 -CH 2 -O-CH 3 , -N(CH 3 )-CH 2 -CH 2 -O-CH 2 - CH 3 , -N(CH 3 )-CH 2 -CH 2 -O-CH 2 -CH 2 -CH 3 , -N(CH 3 )-CH 2 -CH 2 -O-CH(CH 3 ) 2 , -N(CH 3 )-CH 2 -CH 2 -O-CH(CH 3 ) 2 , -N(CH 3 )-CH 2 -CH 2 -O-CH
  • R x is -N(CH 2 CH 3 )-CH 2 -O-CH 3 , - N(CH 2 CH 3 )-CH 2 -O-CH 2 -CH 3 , -N(CH 2 CH 3 )-CH 2 -O-CH 2 -CH 2 -CH 3 , -N(CH 2 CH 3 )-CH 2 -O- CH(CH 3 ) 2 , -N(CH 2 CH 3 )-CH 2 -CH 2 -O-CH 3 , -N(CH 2 CH 3 )-CH 2 -CH 2 -O-CH 2 -CH 3 , -N(CH 2 CH 3 )- CH 2 -CH 2 -O-CH 2 -CH 2 -CH 3 , -N(CH 2 CH 3 )- CH 2 -CH 2 -O-CH 2 -CH 2 -CH 3 , -N(CH 2 CH 3 )-CH 2 -CH 2 -O-CH(CH 3 ) 2
  • R x is - N(CH 2 CH 2 CH 3 )-CH 2 -O-CH 3 , -N(CH 2 CH 2 CH 3 )-CH 2 -O-CH 2 -CH 3 , -N(CH 2 CH 2 CH 3 )-CH 2 -O- CH 2 -CH 2 -CH 3 , -N(CH 2 CH 2 CH 3 )-CH 2 -O-CH(CH 3 ) 2 , -N(CH 2 CH 2 CH 3 )-CH 2 -CH 2 -O-CH 3 , - N(CH 2 CH 2 CH 3 )-CH 2 -CH 2 -O-CH 2 -CH 3 , -N(CH 2 CH 2 CH 3 )-CH 2 -CH 2 -O-CH 2 -CH 3 , - N(CH 2 CH 2 CH 3 )-CH 2 -CH 2 -O-CH 2 -CH 2 -CH 3 , - N(CH 2 CH 2 CH 3 )-CH 2 -
  • R x is -N(CH(CH 3 ) 2 )- CH 2 -O-CH 3 , -N(CH(CH 3 ) 2 )-CH 2 -O-CH 2 -CH 3 , -N(CH(CH 3 ) 2 )-CH 2 -O-CH 2 -CH 2 -CH 3 , - N(CH(CH 3 ) 2 )-CH 2 -O-CH(CH 3 ) 2 , -N(CH(CH 3 ) 2 )-CH 2 -CH 2 -O-CH 3 , -N(CH(CH 3 ) 2 )-CH 2 -CH 2 -O- CH 2 -CH 3 , -N(CH(CH 3 ) 2 )-CH 2 -CH 2 -O-CH 2 -CH 2 -CH 3 , -N(CH(CH 3 ) 2 )-CH 2 -CH 2 -O-CH 2 -CH 2 -CH 3 , -N(CH
  • R x is -N(CH 3 )-CH 2 -CH 2 -O-CH 3 . [0138] In some embodiments, R x is -NH-C(O)-O-(C 1 -C 6 alkyl). In some embodiments, R x is -NH-C(O)-O-(C 1 -C 4 alkyl).
  • R x is -NH-C(O)-O-CH 3 , -NH-C(O)-O- CH 2 CH 3 , -NH-C(O)-O-CH 2 CH 2 CH 3 , -NH-C(O)-O-CH(CH 3 ) 2 , or -NH-C(O)-O-C(CH 3 ) 3 .
  • R x is -O-(C 1 -C 6 alkyl).
  • X is -O-(C 1 -C 3 alkyl).
  • R x is -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In some embodiments, R x is -O-CH 3 . [0140] In some embodiments, R x is -O-(C 1 -C 6 alkyl). In some embodiments, R x is -O-(C 1 - C 3 alkyl). In some embodiments, R x is -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In some embodiments, R x is -O-CH 3 .
  • R x is -O-(C 1 -C 6 alkylene)-NH 2 . In some embodiments, R x is - O-(C 1 -C 3 alkylene)-NH 2 . In some embodiments, R x is -O-CH 2 -NH 2 , -O-CH 2 CH 2 -NH 2 , or -O- CH 2 CH 2 CH 2 -NH 2 . [0142] In some embodiments, R x is -O-(C 1 -C 6 alkylene)-NH-(C 1 -C 6 alkyl).
  • R x is -O-(C 1 -C 3 alkylene)-NH-(C 1 -C 3 alkyl). In some embodiments, R x is -O-CH 2 - NH-CH 3 , -O-CH 2 -NH-CH 2 CH 3 , -O-CH 2 -NH-CH 2 CH 2 CH 3 , or -O-CH 2 -NH-CH(CH 3 ) 2 .
  • R x is -O-CH 2 CH 2 -NH-CH 3 , -O-CH 2 CH 2 -NH-CH 2 CH 3 , -O-CH 2 CH 2 -NH- CH 2 CH 2 CH 3 , or -O-CH 2 CH 2 -NH-CH(CH 3 ) 2 .
  • R x is -O-CH 2 CH 2 CH 2 -NH- CH 3 , -O-CH 2 CH 2 CH 2 -NH-CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -NH-CH 2 CH 2 CH 3 , or -O-CH 2 CH 2 CH 2 -NH- CH(CH 3 ) 2 .
  • R x is -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R x is -O-(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • R x is -O-CH 2 -N(CH 3 ) 2 , -O-CH 2 -N(CH 3 )-CH 2 CH 3 , -O-CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 - N(CH 2 CH 3 )-CH(CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 -N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -O- CH 2 -N(CH(CH 3 ) 2 ) 2 .
  • R x is -O-CH 2 CH 2 -N(CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 3 )- CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , -O-CH 2 CH 2 - N(CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 2 CH 3 )-CH(CH 3 ) 2 , -O- CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 -N(
  • R x is -O-CH 2 CH 2 CH 2 -N(CH 3 ) 2 , -O-CH 2 CH 2 CH 2 - N(CH 3 )-CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -N(CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -N(CH 3 )-CH(CH 3 ) 2 , - O-CH 2 CH 2 CH 2 -N(CH 2 CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 CH 2 - N(CH 2 CH 3 )-CH(CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 2 CH 2 CH 3 ) 2 , -O-CH 2 CH 2 CH 2 -N(CH 2 CH
  • R x is -O-(C 1 -C 6 alkylene)-NH-C(O)-O-(C 1 -C 6 alkyl). In some embodiments, R x is -O-(C 1 -C 3 alkylene)-NH-C(O)-O-(C 1 -C 4 alkyl).
  • R x is -O-CH 2 -NH-C(O)-O-CH 3 , -O-CH 2 -NH-C(O)-O-CH 2 CH 3 , -O-CH 2 -NH-C(O)-O-CH 2 CH 2 CH 3 , - O-CH 2 -NH-C(O)-O-CH(CH 3 ) 2 , or -O-CH 2 -NH-C(O)-O-C(CH 3 ) 3 .
  • R x is - O-CH 2 CH 2 -NH-C(O)-O-CH 3 , -O-CH 2 CH 2 -NH-C(O)-O-CH 2 CH 3 , -O-CH 2 CH 2 -NH-C(O)-O- CH 2 CH 2 CH 3 , -O-CH 2 CH 2 -NH-C(O)-O-CH(CH 3 ) 2 , or -O-CH 2 CH 2 -NH-C(O)-O-C(CH 3 ) 3 .
  • R x is -O-CH 2 CH 2 CH 2 -NH-C(O)-O-CH 3 , -O-CH 2 CH 2 CH 2 -NH-C(O)-O- CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -NH-C(O)-O-CH 2 CH 2 CH 3 , or -O-CH 2 CH 2 CH 2 -NH-C(O)-O- CH(CH 3 ) 2 , or -O-CH 2 CH 2 CH 2 -NH-C(O)-O-C(CH 3 ) 3 .
  • R x is -O-CH 2 CH 2 - NH-C(O)-O-C(CH 3 ) 3 .
  • R x is -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)-C(O)-O-(C 1 -C 6 alkyl). In some embodiments, R x is -O-(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)-C(O)-O-(C 1 -C 4 alkyl).
  • R x is -O-CH 2 -N(CH 3 )-C(O)-O-CH 3 , -O-CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 3 , - O-CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 2 CH 3 , -O-CH 2 -N(CH 3 )-C(O)-O-CH(CH 3 ) 2 , or -O-CH 2 -N(CH 3 )- C(O)-O-C(CH 3 ) 3 .
  • R x is -O-CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 3 , -O-CH 2 CH 2 - N(CH 3 )-C(O)-O-CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 -N(CH 3 )- C(O)-O-CH(CH 3 ) 2 , or -O-CH 2 CH 2 -N(CH 3 )-C(O)-O-C(CH 3 ) 3 .
  • R x is -O- CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 3 , -O-CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 3 , -O- CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH 2 CH 2 CH 3 , -O-CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-CH(CH 3 ) 2 , or -O- CH 2 CH 2 CH 2 -N(CH 3 )-C(O)-O-C(CH 3 ) 3 .
  • R x is -C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R x is -C(O)N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • R x is - C(O)N(CH 3 ) 2 , -C(O)N(CH 3 )-CH 2 CH 3 , -C(O)N(CH 3 )-CH 2 CH 2 CH 3 , -C(O)N(CH 3 )-CH(CH 3 ) 2 , - C(O)N(CH 2 CH 3 ) 2 , -C(O)N(CH 2 CH 3 )-CH 2 CH 2 CH 3 , -C(O)N(CH 2 CH 3 )-CH(CH 3 ) 2 , - C(O)N(CH 2 CH 2 CH 3 ) 2 , -C(O)N(CH 2 CH 2 CH 3 )-CH(CH 3 ) 2 , or -C(O)N(CH(CH 3 ) 2 ) 2 .
  • R x is -C(O)N(CH 3 ) 2 . [0147] In some embodiments, R x is -C(O)O(C 1 -C 6 alkyl). In some embodiments, R x is - C(O)O(C 1 -C 3 alkyl). In some embodiments, R x is -C(O)OCH 3 , -C(O)OCH 2 CH 3 , - C(O)OCH 2 CH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , or -C(O)OC(CH 3 ) 3 . In some embodiments, R x is - C(O)OC(CH 3 ) 3 .
  • R x is oxo.
  • R x is 4- to 10-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl.
  • R x is 4- to 6-membered heterocyclyl optionally substituted by C 1 -C 3 alkyl.
  • R x is 4- to 6-membered heterocyclyl substituted by C 1 -C 3 alkyl.
  • R x is unsubstituted 4- to 6-membered heterocyclyl.
  • the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S.
  • the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 nitrogen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 oxygen atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 sulfur atoms. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom.
  • the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 sulfur atom and 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom and 1 sulfur atom. In some embodiments, R x is 4-membered heterocyclyl optionally substituted by C 1 -C 3 alkyl. In some embodiments, R x is 5-membered heterocyclyl optionally substituted by C 1 -C 3 alkyl. In some embodiments, R x is 6-membered heterocyclyl optionally substituted by C 1 -C 3 alkyl.
  • R x is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, or morpholinyl, each of which is optionally substituted by C 1 -C 3 alkyl.
  • R x is piperazinyl or morpholinyl, each of which is optionally substituted by C 1 -C 3 alkyl.
  • R x is piperazinyl or morpholinyl, each of which is optionally substituted by methyl.
  • R x is piperazinyl substituted by methyl or unsubstituted morpholinyl.
  • X is -NR a R b , -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkylene)-(4- to 10-membered heterocyclyl), or -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and C 6 -C 10 aryl are optionally substituted by 1-5 R x groups; R a and R b are independently H, -C(O)(C 2 -C 6 alkenyl), 4- to 10-membered
  • X is -NR a R b , -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkylene)-(4- to 10-membered heterocyclyl), or -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and C 6 -C 10 aryl are optionally substituted by 1-5 R x groups; R a and R b are independently H, -C(O)(C 2 -C 6 alkenyl), 4- to 10-membered heterocyclyl, or -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C
  • X is -NR a R b ;
  • R a and R b are independently H, -C(O)(C 2 -C 6 alkenyl), 4- to 10-membered heterocyclyl, or -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups, or R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-5 R x groups; and each R x is independently C 1 -C 6 alkyl, C 1
  • R a and R b are independently H, -C(O)(C 2 -C 3 alkenyl), 6- membered heterocyclyl, or -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), wherein the 6- membered heterocyclyl contains 1 nitrogen atom, and is optionally substituted by 1 R x group; and R x is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), or C(O)O(C 1 -C 4 alkyl).
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing one additional nitrogen atom, and wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1-3 R x groups; and each R x is independently C 1 -C 3 alkyl, -NH 2 , -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkyl), -C(O)N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), oxo, or 6-membered heterocyclyl optionally substituted by C 1 -C 3 alkyl.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is optionally substituted by 1-3 R x groups.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is optionally substituted by 1-3 R x groups, wherein each R x is independently -CH 3 , - NH 2 , -N(CH 3 ) 2 , -OCH 3 , -C(O)-N(CH 3 ) 2 , oxo, unsubstituted morpholinyl, or piperizinyl substituted by -CH 3 .
  • X is -NR a R b ;
  • R a and R b are independently H, -C(O)(C 2 -C 6 alkenyl), 4- to 10-membered heterocyclyl, or -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups, or R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-5 R x groups; and each R x is independently halo, C 1 -C
  • R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing one additional nitrogen atom, and wherein the 4- to 6- membered heterocyclyl is optionally substituted by 1-3 R x groups; and each R x is independently halo, C 1 -C 3 alkyl, -NH 2 , -NH-(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 haloalkyl), -N(C 1 -C 3 alkyl)[(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl)], -O-(C 1 -C 3 alkyl), -C(O)N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl)(C 1
  • R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is optionally substituted by 1-3 R x groups.
  • R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is optionally substituted by 1-3 R x groups, wherein each R x is independently -F, -CH 3 , -NH 2 , - N(H)-(CH 3 ), -N(CH 3 ) 2 , -N(CH 3 )-CH 2 -CHF 2 , -N(CH 3 )-CH 2 -CF 3 , -N(CH 3 )-CH 2 -CH 2 -O-CH 3 , - OCH 3 , -C(O)-N(CH 3 ) 2 , oxo, unsubstituted morpholinyl, or piperizinyl substituted by -CH 3 .
  • X is -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O- (C 1 -C 6 alkylene)-(4- to 10-membered heterocyclyl), or -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and C 6 -C 10 aryl are optionally substituted by 1-5 R x groups, and each R x is independently C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-NH 2 , -NH 2 , or -O-(C 1 -C 6 alkylene)-
  • X is -O-(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -O- (C 1 -C 3 alkylene)-(5- to 6-membered heterocyclyl), or -O-(C 1 -C 3 alkylene)-(phenyl), wherein the 5- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O, and wherein the 5- to 6-membered heterocyclyl and phenyl are optionally substituted by 1-3 R x groups, and each R x is independently C 1 -C 3 alkyl, -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), - (C 1 -C 3 alkylene)-NH 2 , -NH 2 , or -O-(C 1 -C 3 alkylene)-NH-C(O)-O-(
  • the 5- to 6-membered heterocyclyl is pyrrolidinyl or morpholinyl.
  • X is -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O- (C 1 -C 6 alkylene)-(4- to 10-membered heterocyclyl), or -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and C 6 -C 10 aryl are optionally substituted by 1-5 R x groups, and each R x is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -(C 1 -C 6 alkylene)-O-
  • X is -O-(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkylene)-(4- to 6-membered heterocyclyl), or -O-(C 1 -C 3 alkylene)-(phenyl), wherein the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O, and wherein the 4- to 6-membered heterocyclyl and phenyl are optionally substituted by 1-3 R x groups, and each R x is independently C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), -(C 1 -C 3 alkylene)-NH 2 , -NH 2 , or -O- (C 1 -C 3 alky
  • X is -O-(C 1 -C 3 alkylene)- N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -O-(C 1 -C 2 alkylene)-(4- to 6-membered heterocyclyl), or -O-(C 1 -C 2 alkylene)-(phenyl), wherein the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O, and wherein the 4- to 6-membered heterocyclyl and phenyl are optionally substituted by 1-2 R x groups, and each R x is independently C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, -(C 1 -C 2 alkylene)-O-(C 1 -C 2 alkyl), -(C 1 -C 2 alkylene)-NH 2 , -NH 2 , or -O- (C 1 -C 2 alky
  • the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl or morpholinyl. In some embodiments, the 4- to 6- membered heterocyclyl is azetidinyl. In some embodiments, the 4- to 6-membered heterocyclyl is pyrrolidinyl. In some embodiments, the 4- to 6-membered heterocyclyl is morpholinyl.
  • X is -O-CH 2 -(pyrrolidinyl), -O-CH 2 CH 2 -(pyrrolidinyl), -O- CH 2 -(morpholinyl), or -O-CH 2 CH 2 -(morpholinyl), wherein the pyrrolidinyl and morpholinyl are optionally substituted by 1-2 C 1 -C 3 alkyl groups.
  • X is -O-CH 2 - (pyrrolidinyl), -O-CH 2 CH 2 -(pyrrolidinyl), -O-CH 2 -(morpholinyl), or -O-CH 2 CH 2 -(morpholinyl), wherein the pyrrolidinyl and morpholinyl are optionally substituted by -CH 3 , -CH 2 CH 3 , CH(CH 3 ) 2 , or -CH 2 CH 2 -O-CH 3 .
  • X is -O-CH 2 -(azetidinyl) or -O-CH 2 - (pyrrolidinyl), wherein the azetidinyl and pyrrolidinyl are optionally substituted by 1-2 C 1 -C 3 haloalkyl groups.
  • X is -O-CH 2 -(azetidinyl) or -O-CH 2 -(pyrrolidinyl), wherein the azetidinyl and pyrrolidinyl are optionally substituted by -CH 2 CHF 2 or -CH 2 CF 3 .
  • X is -O-CH 2 -(phenyl) or -O-CH 2 CH 2 -(phenyl), wherein the phenyl is optionally substituted by -CH 2 -NH 2 , -NH 2 , or -O-CH 2 CH 2 -NH-C(O)-O-(t-butyl).
  • X is -O-pyrrolidinyl, wherein the pyrrolidinyl is substituted by 1-2 groups selected from the group consisting of C 1 -C 3 alkyl and -O-( C 1 -C 3 alkyl).
  • X is -O- pyrrolidinyl, wherein the pyrrolidinyl is substituted by -CH 3 and -O-CH 3 .
  • X is selected from the group consisting of :
  • X is selected from the group consisting of:
  • R 1 is H, C 1 -C 6 alkyl-CN, -C 1 -C 6 alkylene-O-(C 1 -C 6 alkyl), or C 1 -C 6 haloalkyl.
  • R 1 is H.
  • R 1 is C 1 -C 6 alkyl-CN.
  • R 1 is C 1 -C 6 alkyl-CN containing 1-6 cyano groups.
  • R 1 is C 1 -C 6 alkyl-CN containing 1 cyano group.
  • R 1 is C 1 -C 6 alkyl-CN containing 2 cyano groups.
  • R 1 is C 1 -C 6 alkyl-CN containing 3 cyano groups. In some embodiments, R 1 is C 1 -C 3 alkyl-CN. In some embodiments, R 1 is C 1 -C 3 alkyl-CN containing 1-3 cyano groups. In some embodiments, R 1 is C 1 -C 3 alkyl-CN containing 1 cyano group.
  • R 1 is -CH 2 CN, -CH 2 CH 2 CN, -CH(CN)CH 3 , -CH 2 CH 2 CH 2 CN, -CH 2 CH(CN)CH 3 , - CH(CN)CH 2 CH 3 , -C(CH 3 ) 2 CN, or -CH(CH 2 CN)(CH 3 ).
  • R 1 is -CH 2 CN.
  • R 1 is -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl).
  • R 1 is -(C 1 -C 3 alkylene)-O-(C 1 -C 6 alkyl).
  • R 1 is -(C 1 -C 6 alkylene)-O-(C 1 -C 3 alkyl). In some embodiments, R 1 is -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl). In some embodiments, R 1 is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O- CH(CH 3 ) 2 .
  • R 1 is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O- CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R 1 is -CH 2 CH 2 CH 2 -OCH 3 , - CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -OCH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -OCH(CH 3 ) 2 .
  • R 1 is C 1 -C 6 haloalkyl.
  • R 1 is C 1 -C 6 haloalkyl containing 1-13 halogen atoms. In some embodiments, R 1 is C 1 -C 3 haloalkyl. In some embodiments, R 1 is C 1 -C 3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R 1 is C 1 -C 2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of fluoro, chloro, and bromo atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of fluoro and chloro atoms.
  • the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of fluoro and chloro atoms.
  • R 1 is -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 , -CH 2 Cl, or -CHFCl. [0164] In some embodiments, R 1 is H or -CH 2 CN.
  • R 2 is H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkylene-O-(C 1 -C 6 alkyl), -C(O)NH 2 , -C(O)NH-(C 1 -C 6 alkyl), or -C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
  • R 2 is H.
  • R 2 is halo.
  • R 2 is F, Cl, or Br.
  • R 2 is F.
  • R 2 is cyano.
  • R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is C 1 -C 3 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. [0170] In some embodiments, R 2 is -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl). In some embodiments, R 2 is -(C 1 -C 3 alkylene)-O-(C 1 -C 6 alkyl). In some embodiments, R 2 is -(C 1 -C 6 alkylene)-O-(C 1 -C 3 alkyl).
  • R 2 is -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl). In some embodiments, R 2 is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O- CH(CH 3 ) 2 . In some embodiments, R 2 is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O- CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R 2 is -CH 2 CH 2 CH 2 -O-CH 3 , - CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R 2 is -C(O)NH 2 .
  • R 2 is -C(O)NH-(C 1 -C 6 alkyl).
  • R 2 is - C(O)NH-(C 1 -C 3 alkyl).
  • R 2 is -C(O)NH-(methyl).
  • R 2 is -C(O)NH-(ethyl). In some embodiments, R 2 is -C(O)NH-(n-propyl). In some embodiments, R 2 is -C(O)NH-(isopropyl). [0173] In some embodiments, R 2 is -C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, R 2 is -C(O)N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
  • R 2 is - C(O)N(methyl)(methyl), -C(O)N(methyl)(ethyl), -C(O)N(methyl)(n-propyl), - C(O)N(methyl)(isopropyl), -C(O)N(ethyl)(ethyl), -C(O)N(ethyl)(n-propyl), - C(O)N(ethyl)(isopropyl), -C(O)N(n-propyl)(n-propyl), -C(O)N(n-propyl)(isopropyl), or - C(O)N(isopropyl)(isopropyl).
  • R 3 is H, C 1 -C 6 alkyl, or -(C 1 -C 6 alkylene)-NR 3A R 3B .
  • R 3 is H.
  • R 3 is C 1 -C 6 alkyl.
  • R 3 is C 1 -C 3 alkyl.
  • R 3 is methyl, ethyl, n-propyl, or isopropyl.
  • R 3 is - CH 3 .
  • R 3 is -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl).
  • R 3 is -(C 1 -C 3 alkylene)-O-(C 1 -C 6 alkyl). In some embodiments, R 3 is -(C 1 -C 6 alkylene)-O-(C 1 -C 3 alkyl). In some embodiments, R 3 is -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl). In some embodiments, R 3 is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O- CH(CH 3 ) 2 .
  • R 3 is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O- CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R 3 is -CH 2 CH 2 CH 2 -O-CH 3 , - CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R 3 is -CH 2 -O-CH 3 , [0178] In some embodiments, R 3 is -O-(C 1 -C 6 alkyl). In some embodiments, R 3 is -O-(C 1 - C 3 alkyl). In some embodiments, R 3 is -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In some embodiments, R 3 is -O-CH 3 . [0179] In some embodiments, R 3 is -(C 1 -C 3 alkylene)-NR 3A R 3B .
  • R 3 is -CH 2 -NR 3A R 3B . In some embodiments, R 3 is -CH 2 CH 2 -NR 3A R 3B . In some embodiments, R 3 is -CH 2 CH 2 CH 2 -NR 3A R 3B .
  • R 3A and R 3B are independently H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, wherein the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy; or R 3A and R 3B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing 1 additional heteroatom selected from the group consisting of N, O, and S, wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkyl.
  • R 3A and R 3B are independently H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, wherein the C 1 -C 6 alkyl is optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy; or R 3A and R 3B are taken together with the nitrogen atom to which they are attached to form a 4- to 10- membered heterocyclyl optionally containing 1 additional heteroatom selected from the group consisting of N, O, and S, wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkyl.
  • R 3A is H.
  • R 3A is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy.
  • R 3A is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy.
  • R 3A is C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy. In some embodiments, R 3A is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy.
  • R 3A is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy.
  • R 3A is C 1 -C 6 alkyl optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy.
  • R 3A is C 1 -C 6 alkyl optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy. In some embodiments, R 3A is C 1 -C 3 alkyl optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy. In some embodiments, R 3A is methyl, ethyl, n-propyl, or isopropyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy.
  • R 3A is unsubstituted C 1 -C 6 alkyl. In some embodiments, R 3A is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 3A is methyl, ethyl, n-propyl, or isopropyl, each of which is unsubstituted. In some embodiments, R 3A is -CH 3 . [0186] In some embodiments, R 3A is C 1 -C 6 alkyl substituted by 1-5 halo groups. In some embodiments, R 3A is C 1 -C 3 alkyl substituted by 1-5 halo groups.
  • R 3A is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 groups selected from the group consisting of F, Cl, Br, and I. [0187] In some embodiments, R 3A is C 1 -C 6 alkyl substituted by 1-5 hydroxyl groups. In some embodiments, R 3A is C 1 -C 3 alkyl substituted by 1-5 hydroxyl groups. In some embodiments, R 3A is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 hydroxyl groups.
  • R 3A is methyl-OH, ethyl-OH, n-propyl-OH, or isopropyl-OH. In some embodiments, R 3A is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CH 2 OH, - CH(OH)CH 2 CH 3 , -CH 2 CH(OH)CH 3 , -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 OH, or -CH(CH 2 OH)(CH 3 ). [0188] In some embodiments, R 3A is C 1 -C 6 alkyl substituted by 1-5 cyano groups.
  • R 3A is C 1 -C 3 alkyl substituted by 1-5 cyano groups. In some embodiments, R 3A is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 cyano groups. In some embodiments, R 3A is methyl-CN, ethyl-CN, n-propyl-CN, or isopropyl-CN.
  • R 3A is -CH 2 CN, -CH(CN)CH 3 , -CH 2 CH 2 CN, -CH(CN)CH 2 CH 3 , - CH 2 CH(CN)CH 3 , -CH 2 CH 2 CH 2 CN, -C(CH 3 ) 2 CN, or -CH(CH 2 CN)(CH 3 ) .
  • R 3A is C 1 -C 6 alkyl substituted by 1-5 C 1 -C 6 alkoxy groups. In some embodiments, R 3A is C 1 -C 3 alkyl substituted by 1-5 C 1 -C 6 alkoxy groups.
  • R 3A is C 1 -C 6 alkyl substituted by 1-5 C 1 -C 3 alkoxy groups. In some embodiments, R 3A is C 1 -C 3 alkyl substituted by 1-5 C 1 -C 3 alkoxy groups. In some embodiments, R 3A is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 C 1 -C 3 alkoxy groups. In some embodiments, R 3A is -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 -O- CH(CH 3 ) 2 .
  • R 3A is -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O- CH 2 CH 2 CH 3 , or -CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R 3A is -CH 2 CH 2 CH 2 -O-CH 3 , - CH 2 CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 CH 2 -O-CH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -O-CH(CH 3 ) 2 .
  • R 3A is -CH(CH 3 )CH 2 -O-CH 3 , -CH(CH 3 )CH 2 -O-CH 2 CH 3 , -CH(CH 3 )CH 2 -O- CH 2 CH 2 CH 3 , or -CH(CH 3 )CH 2 -O-CH(CH 3 ) 2 .
  • R 3A is -CH 2 CH(CH 3 )-O- CH 3 , -CH 2 CH(CH 3 )-O-CH 2 CH 3 , -CH 2 CH(CH 3 )-O-CH 2 CH 2 CH 3 , or -CH 2 CH(CH 3 )-O-CH(CH 3 ) 2 .
  • R 3A is C 3 -C 6 cycloalkyl optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy. In some embodiments, R 3A is C 3 -C 6 cycloalkyl optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy.
  • R 3A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy. [0191] In some embodiments, R 3A is unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, R 3A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is unsubstituted.
  • R 3A is C 3 -C 6 cycloalkyl substituted by 1-5 halo groups.
  • R 3A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 groups selected from the group consisting of F, Cl, Br, and I.
  • R 3A is C 3 -C 6 cycloalkyl substituted by 1-5 hydroxyl groups.
  • R 3A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 hydroxyl groups.
  • R 3A is C 3 -C 6 cycloalkyl substituted by 1-5 cyano groups. In some embodiments, R 3A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 cyano groups. [0195] In some embodiments, R 3A is C 3 -C 6 cycloalkyl substituted by 1-5 C 1 -C 6 alkoxy groups. In some embodiments, R 3A is C 3 -C 6 cycloalkyl substituted by 1-5 C 1 -C 3 alkoxy groups.
  • R 3A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 C 1 -C 3 alkoxy groups.
  • R 3B is H.
  • R 3B is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy.
  • R 3B is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy. In some embodiments, R 3B is C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy.
  • R 3B is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy.
  • R 3B is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy.
  • R 3B is C 1 -C 6 alkyl optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy. In some embodiments, R 3B is C 1 -C 6 alkyl optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy. In some embodiments, R 3B is C 1 -C 3 alkyl optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy.
  • R 3B is methyl, ethyl, n-propyl, or isopropyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy. [0199] In some embodiments, R 3B is unsubstituted C 1 -C 6 alkyl. In some embodiments, R 3B is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 3B is methyl, ethyl, n-propyl, or isopropyl, each of which is unsubstituted. In some embodiments, R 3B is -CH 3 .
  • R 3B is C 1 -C 6 alkyl substituted by 1-5 halo groups. In some embodiments, R 3B is C 1 -C 3 alkyl substituted by 1-5 halo groups. In some embodiments, R 3B is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 groups selected from the group consisting of F, Cl, Br, and I. [0201] In some embodiments, R 3B is C 1 -C 6 alkyl substituted by 1-5 hydroxyl groups. In some embodiments, R 3B is C 1 -C 3 alkyl substituted by 1-5 hydroxyl groups.
  • R 3B is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 hydroxyl groups. In some embodiments, R 3B is methyl-OH, ethyl-OH, n-propyl-OH, or isopropyl-OH. In some embodiments, R 3B is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CH 2 OH, - CH(OH)CH 2 CH 3 , -CH 2 CH(OH)CH 3 , -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 OH, or -CH(CH 2 OH)(CH 3 ).
  • R 3B is C 1 -C 6 alkyl substituted by 1-5 cyano groups. In some embodiments, R 3B is C 1 -C 3 alkyl substituted by 1-5 cyano groups. In some embodiments, R 3B is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 cyano groups. In some embodiments, R 3B is methyl-CN, ethyl-CN, n-propyl-CN, or isopropyl-CN.
  • R 3B is -CH 2 CN, -CH(CN)CH 3 , -CH 2 CH 2 CN, -CH(CN)CH 2 CH 3 , - CH 2 CH(CN)CH 3 , -CH 2 CH 2 CH 2 CN, -C(CH 3 ) 2 CN, or -CH(CH 2 CN)(CH 3 ) .
  • R 3B is C 1 -C 6 alkyl substituted by 1-5 C 1 -C 6 alkoxy groups. In some embodiments, R 3B is C 1 -C 3 alkyl substituted by 1-5 C 1 -C 6 alkoxy groups.
  • R 3B is C 1 -C 6 alkyl substituted by 1-5 C 1 -C 3 alkoxy groups. In some embodiments, R 3B is C 1 -C 3 alkyl substituted by 1-5 C 1 -C 3 alkoxy groups. In some embodiments, R 3B is methyl, ethyl, n-propyl, or isopropyl, each of which is substituted by 1-3 C 1 -C 3 alkoxy groups. In some embodiments, R 3B is -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -OCH 2 CH 2 CH 3 , or -CH 2 -OCH(CH 3 ) 2 .
  • R 3B is -CH 2 CH 2 -OCH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -OCH 2 CH 2 CH 3 , or -CH 2 CH 2 -OCH(CH 3 ) 2 .
  • R 3B is -CH 2 CH 2 CH 2 -OCH 3 , -CH 2 CH 2 CH 2 -O- CH 2 CH 3 , -CH 2 CH 2 CH 2 -OCH 2 CH 2 CH 3 , or -CH 2 CH 2 CH 2 -OCH(CH 3 ) 2 .
  • R 3B is -CH(CH 3 )CH 2 -OCH 3 , -CH(CH 3 )CH 2 -O-CH 2 CH 3 , -CH(CH 3 )CH 2 -OCH 2 CH 2 CH 3 , or - CH(CH 3 )CH 2 -OCH(CH 3 ) 2 .
  • R 3B is -CH 2 CH(CH 3 )-OCH 3 , -CH 2 CH(CH 3 )- O-CH 2 CH 3 , -CH 2 CH(CH 3 )-OCH 2 CH 2 CH 3 , or -CH 2 CH(CH 3 )-OCH(CH 3 ) 2 .
  • R 3B is C 3 -C 6 cycloalkyl optionally substituted by 1-5 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy. In some embodiments, R 3B is C 3 -C 6 cycloalkyl optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkoxy.
  • R 3B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 3 alkoxy. [0205] In some embodiments, R 3B is unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, R 3B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is unsubstituted. In some embodiments, R 3B is unsubstituted cyclopropyl.
  • R 3B is C 3 -C 6 cycloalkyl substituted by 1-5 halo groups.
  • R 3B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 groups selected from the group consisting of F, Cl, Br, and I.
  • R 3B is C 3 -C 6 cycloalkyl substituted by 1-5 hydroxyl groups.
  • R 3B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 hydroxyl groups.
  • R 3B is C 3 -C 6 cycloalkyl substituted by 1-5 cyano groups. In some embodiments, R 3B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 cyano groups. [0209] In some embodiments, R 3B is C 3 -C 6 cycloalkyl substituted by 1-5 C 1 -C 6 alkoxy groups. In some embodiments, R 3B is C 3 -C 6 cycloalkyl substituted by 1-5 C 1 -C 3 alkoxy groups.
  • R 3B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1-3 C 1 -C 3 alkoxy groups.
  • R 3A and R 3B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing 1 additional heteroatom selected from the group consisting of N, O, and S, wherein the 4- to 10- membered heterocyclyl is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkyl.
  • R 3A and R 3B are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing 1 additional heteroatom selected from the group consisting of N, O, and S, wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkyl.
  • R 3A and R 3B are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing 1 additional heteroatom selected from the group consisting of N, O, and S, wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1-3 groups independently selected from the group consisting of F, Cl, Br, hydroxyl, cyano, methyl, ethyl, n-propyl, and isopropyl.
  • the 4- to 6- membered heterocyclyl contains 1 nitrogen atom.
  • the 4- to 6-membered heterocyclyl contains 2 nitrogen atoms.
  • the 4- to 6-membered heterocyclyl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the 4- to 6- membered heterocyclyl contains 1 nitrogen atom and 1 sulfur atom. In some embodiments, the 4- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, imidazolidinyl, mopholinyl, or thiomorpholinyl.
  • R 3 is C 1 -C 3 alkyl, -(C 1 -C 3 alkylene)-NR 3A R 3B , -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), or -O-(C 1 -C 3 alkyl), and R 3A and R 3B are independently C 1 -C 3 alkyl, or R 3A and R 3B are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally containing 1 additional oxygen atom, wherein the 4- to 6- membered heterocyclyl is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkyl.
  • R 3 is C 1 -C 2 alkyl, -(C 1 -C 2 alkylene)-NR 3A R 3B , -(C 1 -C 2 alkylene)-O-(C 1 -C 2 alkyl), or -O-(C 1 -C 2 alkyl), and R 3A and R 3B are independently C 1 -C 2 alkyl, or R 3A and R 3B are taken together with the nitrogen atom to which they are attached to form a 5- to 6-membered heterocyclyl optionally containing 1 additional oxygen atom, wherein the 5- to 6-membered heterocyclyl is optionally substituted by 1-3 groups independently selected from the group consisting of halo, hydroxyl, cyano, and C 1 -C 6 alkyl.
  • the 5- to 6-membered heterocyclyl is unsubstituted. In some embodiments, the 5- to 6-membered heterocyclyl is pyrrolidinyl or morpholinyl.
  • R 3 is selected from the group consisting of : [0213] In some embodiments, the moiety is . [0214] In some embodiments, R 4 is H. [0215] In some embodiments, R 4 is C 1 -C 6 alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 4 is methyl. [0216] In some embodiments, the compound of formula (I’) is a compound of formula (II’- A2-i) or formula (II’-A2-ii):
  • the compound of formula (I) is a compound of formula (II- A2-i) or formula (II-A2-ii): wherein R A , R B , and X are as defined for formula (I).
  • the compound of formula (I’) is a compound of formula (II’- B2-i) or formula (II’-B2-ii): wherein X is as defined for formula (I’), p is 0, 1 or 2, q is 0 or 1, and each R c , if present, is independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH- C(O)(C 1 -C 6 alkyl), -NH-S(O)(C 1 -C 6 alkyl), -NH-S(O) 2 (C 1 -C 6 alkyl), -N(C 1 -C
  • q is 0. In some embodiments, q is 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R c , if present, is F, Cl, or Br. In some embodiments, R c , if present, is F. In some embodiments, R c , if present, is Cl. In some embodiments, R c , if present, is Br. In some embodiments, R c , if present, is hydroxy. In some embodiments, R c , if present, is methyl. In some embodiments, R c , if present, is methoxy.
  • the R c if present, is on the phenyl ring of the indolinly or tetrahydroquinolinyl ring.
  • the compound of formula (I’) is a compound of formula (II’- B2-i) or formula (II’-B2-ii): wherein p is 0, 1, or 2, q is 0 or 1, and each R c , if present, is independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl), -NH-S(O)(C 1 - C
  • q is 0. In some embodiments, q is 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R c , if present, is F, Cl, or Br. In some embodiments, R c , if present, is F. In some embodiments, R c , if present, is Cl. In some embodiments, R c , if present, is Br. In some embodiments, R c , if present, is hydroxy. In some embodiments, R c , if present, is oxo. In some embodiments, R c , if present, is methyl.
  • R c if present, is methoxy. In some embodiments, the R c , if present, is on the phenyl ring of the indolinly or tetrahydroquinolinyl ring. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiment, R x is C 1 -C 6 alkyl (e.g., methyl). In some embodiment, R x is -NH 2 . In some embodiment, R x is -NH(C 1 -C 6 alkyl) (e.g., -NHCH 3 ).
  • R x is -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiment, R x is -N(CH 3 ) 2 . In some embodiment, R x is -N(CH 3 )(CH 2 CH 3 ). In some embodiment, R x is -N(C 1 -C 6 alkyl)(C 1 -C 6 haloalkyl). In some embodiment, R x is -N(CH 3 )(CH 2 CHF 2 ). In some embodiment, R x is - N(CH 3 )(CH 2 CF 3 ).
  • R x is -O-(C 1 -C 6 alkyl) (e.g., -O-CH 3 ). In some embodiment, R x is oxo. In some embodiments, z is 1, and R x is -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl). In some embodiments, z is 1, and R x is -N(CH 3 ) 2 . In some embodiments, z is 1, and R x is - N(CH 3 )(CH 2 CHF 2 ). In some embodiments, z is 1, and R x is -N(CH 3 )(CH 2 CF 3 ).
  • z is 1, and R x is C 1 -C 6 alkyl (e.g., methyl). In some embodiments, z is 2, and one R x is C 1 -C 6 alkyl (e.g., methyl) and the other R x is -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl) (e.g., -N(CH 3 ) 2 ).
  • the compound of formula (I’) is a compound of formula (II’- B3-i) or formula (II’-B3-ii):
  • each R c is independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl), -NH-S(O)(C 1 - C 6 alkyl), -NH-S(O) 2 (C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)S(O)(C 1 - C 6 alkyl), and -N(C 1 -C 6 alkyl), and -N(C 1 -C 6 alkyl
  • q is 0. In some embodiments, q is 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R c , if present, is F, Cl, or Br. In some embodiments, R c , if present, is F. In some embodiments, R c , if present, is Cl. In some embodiments, R c , if present, is Br. In some embodiments, R c , if present, is hydroxy. In some embodiments, R c , if present, is oxo. In some embodiments, R c , if present, is methyl.
  • R c if present, is methoxy. In some embodiments, the R c , if present, is on the phenyl ring of the indolinly or tetrahydroquinolinyl ring. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiment, R x is C 1 - C 6 alkyl. In some embodiments, R x is methyl. In some embodiments, R x is ethyl. In some embodiments, R x is n-propy. In some embodiments, R x is isopropyl.
  • R x is C 1 -C 6 haloalkyl (e.g., C 1 -C 3 haloalkyl). In some embodiments, R x is C 2 haloalkyl. In some embodiments, R x is -CH 2 CHF 2 . In some embodiments, R x is -CH 2 CF 3 . [0221] In some embodiments, the compound of formula (I’) is a compound of formula (II’- B4-i) or formula (II’-B4-ii):
  • each R c is independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 -C 6 alkyl), -NH-S(O)(C 1 - C 6 alkyl), -NH-S(O) 2 (C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)S(O)(C 1 - C 6 alkyl), and -N(C 1 -C 6 alkyl), and -N(C 1 -C 6 alkyl
  • q is 0. In some embodiments, q is 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R c , if present, is F, Cl, or Br. In some embodiments, R c , if present, is F. In some embodiments, R c , if present, is Cl. In some embodiments, R c , if present, is Br. In some embodiments, R c , if present, is hydroxy. In some embodiments, R c , if present, is oxo. In some embodiments, R c , if present, is methyl.
  • R c if present, is methoxy. In some embodiments, the R c , if present, is on the phenyl ring of the indolinly or tetrahydroquinolinyl ring. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiment, R x is - NH 2 . In some embodiment, R x is -(C 1 -C 6 alkylene)-NH 2 (e.g., -CH 2 -NH 2 ).
  • the compound of formula (I’) is a compound of wherein R Q corresponds to the –N(R A )(R B ) moiety of the compound of formula (I’), and R 1 and X are as defined for formula (I’).
  • the compound of formula (I’) is a compound of wherein R corresponds to the moiety of the compound of formula (I’).
  • the compound of formula (I’) is a compound of
  • R Q corresponds to the –N(R A )(R B ) moiety of the compound of formula (I’), and X is as defined for formula (I’).
  • salts of compounds disclosed herein such as pharmaceutically acceptable salts.
  • the present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.
  • a particular stereochemical form such as a specific enantiomeric form or diastereomeric form
  • any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of that same compound are herein described.
  • tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
  • the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
  • the disclosure also intends 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.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I’) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of 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, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl.
  • Certain isotope labeled compounds e.g. 3 H and 14 C
  • are useful in compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deuterium ( 2 H) 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.
  • Isotopically-labeled compounds described herein 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.
  • the disclosure also includes any or all metabolites of any of the compounds described.
  • the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
  • Solvates of a compound provided herein or a salt thereof are also contemplated.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0.5% impurity.
  • the container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
  • the compounds and compositions detailed herein are orally bioavailable. However, the compounds and compositions may also be formulated for parenteral (e.g., intravenous) administration.
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.
  • compositions and Formulations [0234] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure.
  • the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided.
  • a compound detailed herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
  • a compound detailed herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000), which is incorporated herein by reference.
  • a compound detailed herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • examples of carriers, which may be used for the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • compositions comprising a compound provided herein are also described.
  • the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.
  • Methods of Use Compounds as detailed herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or compositions as detailed herein, such as a pharmaceutical composition containing a compound provided herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • in vitro methods such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • methods of using the compounds or compositions detailed herein to treat disease conditions including but not limited to conditions implicated by RAS, including KRAS, HRAS and NRAS, and including mutants such as KRasG12C.
  • provided herein is a method for inhibiting RAS, including KRAS, HRAS and NRAS, activity in a cell, comprising contacting the cell in which inhibition of said RAS activity is desired with an effective amount of a compound of any formula provided herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing or pharmaceutical composition containing the compound or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing.
  • the contacting is in vitro. In some embodiments, the contacting is in vivo.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a KRAS G12C with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRAS G12C as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing KRAS G12C.
  • a cell in which inhibition of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), activity is desired is contacted with an effective amount of a compound provided herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, to negatively modulate the activity of said RAS.
  • RAS including KRAS, HRAS and NRAS
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced said RAS activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C) .
  • RAS including KRAS, HRAS and NRAS
  • the degree of covalent modification of RAS, including KRAS, HRAS and NRAS may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), activity of the amount of phosphylated ERK to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
  • RAS including KRAS, HRAS and NRAS (e.g., KRasG12C)
  • NRAS e.g., KRasG12C
  • the compound or a pharmaceutically acceptable salt thereof, or the composition is administered to the individual according to a dosage and/or method of administration described herein. In some embodiments, the method further comprises administering to the individual an additional therapeutic agent. Also provided herein is the use of a compound or a composition disclosed herein for the preparation of a medicament for treating a disease or disorder mediated by RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C). [0247] Compounds and compositions detailed herein can inhibit the activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C).
  • a compound or a composition disclosed herein can be used to inhibit activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), in a cell or in an individual or patient in need of inhibition of the protein by administering an inhibiting amount of the compound or the composition to the cell, individual, or patient.
  • RAS including KRAS, HRAS and NRAS
  • NRAS e.g., KRasG12C
  • the cancer is associated with mutations, activation, or involvement of the RAS, including KRAS, HRAS and NRAS, pathway, especially those associated with or dependent on G12C mutant RAS.
  • the cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds and compositions detailed herein but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the cancer is non-small cell lung cancer or pancreatic cancer.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, gall bladder cancer, thyroid cancer, or bile duct cancer.
  • a method of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a compound or a composition disclosed herein.
  • use of a compound or a composition disclosed herein for the preparation of a medicament for treating cancer is also provided herein.
  • Compounds and compositions detailed herein can treat RASopathies.
  • the RASopathies include apillary malformation-AV malformation syndrome, autoimmune lymphoproliferative syndrome, cardiofaciocutaneous syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, Noonan syndrome, Costello syndrome, Legius syndrome, or Noonan syndrome with multiple lentigines.
  • the disclosed compounds inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another embodiment the disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a pharmaceutical composition of comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier to a subject in need thereof.
  • KRAS, HRAS or NRAS G12C mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow and/or lymph nodes). Accordingly, certain embodiments are directed to administration of disclosed compounds (e.g., in the form of a pharmaceutical composition) to a patient in need of treatment of a hematological malignancy.
  • hematological malignancies e.g., cancers that affect blood, bone marrow and/or lymph nodes.
  • Such malignancies include, but are not limited to leukemias and lymphomas.
  • the presently disclosed compounds can be used for treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and/ or other leukemias.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • CML chronic myelogenous leukemia
  • AoL acute monocytic leukemia
  • the compounds are useful for treatment of lymphomas such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.
  • the compounds are useful for treatment of plasma cell malignancies such as multiple myeloma mantle cell lymphoma and Waldenstrom’s macroglubunemia.
  • Determining whether a tumor or cancer comprises a Gl2C KRAS, HRAS or NRAS mutation can be undertaken by assessing the nucleotide sequence encoding the KRAS, HRAS or NRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the characteristics of a putative KRAS, HRAS or NRAS mutant protein.
  • the sequence of wild-type human KRAS, HRAS or NRAS is known in the art (e.g., Accession No. NP203524).
  • Methods for detecting a mutation in a RAS such as KRAS, HRAS or NRAS (e.g., KRasG12C), nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to, polymeRASe chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymeRASe chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses.
  • PCR-RFLP polymeRASe chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymeRASe chain reaction-
  • samples are evaluated for KRAS, HRAS or NRAS mutations (e.g., KRasG12C mutations) by real-time PCR.
  • fluorescent probes specific for the KRAS, HRAS or NRAS mutation e.g., KRasG12C mutation
  • the probe binds and fluorescence is detected.
  • the KRAS, HRAS or NRAS mutation e.g., KRasG12C mutation
  • Methods for detecting a mutation in a RAS such as KRAS, HRAS or NRAS (e.g., KRasG12C), protein are known by those of skill in the art. These methods include, but are not limited to, detection of a RAS, such as KRAS, HRAS or NRAS (e.g., KRasG12C), mutant using a binding agent (e.g. an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.
  • Methods for determining whether a tumor or cancer comprises a RAS including KRAS, HRAS or NRAS (e.g., KRasG12C), mutation can use a variety of samples.
  • the sample is taken from a subject having a tumor or cancer.
  • the sample is a fresh tumor/cancer sample.
  • the sample is a frozen tumor/cancer sample.
  • the sample is a formalin-fixed paraffin- embedded sample.
  • the sample is processed to a cell lysate.
  • the sample is processed to DNA or RNA.
  • Embodiments also relate to a method of treating a hyperproliferative disorder in an individual that comprises administering to said individual a therapeutically effective amount of a compound or a composition disclosed herein.
  • said method relates to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g, Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal.
  • cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g, Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal.
  • cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g, Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal.
  • AIDS-related cancers
  • bile duct cancer bladder cancer
  • bone cancer brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T- cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder
  • said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • BPH benign prostatic hypertrophy
  • provided herein are methods of inhibiting protein activity by contacting the G12C mutant RAS, including KRAS, HRAS and NRAS, protein with an effective amount of a compound or a composition detailed herein in solution.
  • methods of inhibiting protein activity in subject including but not limited to rodents and mammal (e.g., human) by administering into the subject an effective amount of a compound or a composition detailed herein.
  • the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the individual is a human. In some embodiments, the individual has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the individual has been identified or diagnosed as having a cancer having a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the individual has a tumor that is positive for a KRAS G12C mutation (e.g., as determined using a regulatory agency- approved assay or kit). In some embodiments, the individual is suspected of having a KRAS G12C gene-associated cancer. In some embodiments, the individual has a clinical record indicating that the individual has a tumor that has a KRAS G12C mutation (and optionally the clinical record indicates that the individual should be treated with any of the compositions provided herein).
  • RAS including KRAS, HRAS and NRAS (e.g., KRasG12C)
  • NRAS e.g., KRasG12C
  • methods of inhibiting RAS, including KRAS, HRAS and NRAS e.g., KRasG12C
  • a compound or a composition detailed herein sufficient to inhibit the activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), in said cell.
  • provided herein are methods of inhibiting RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), activity in a tissue by contacting said tissue with an amount of a compound or a composition detailed herein sufficient to inhibit the activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), in said tissue.
  • RAS including KRAS, HRAS and NRAS
  • RAS including KRAS, HRAS and NRAS (e.g., KRasG12C)
  • NRAS e.g., KRasG12C
  • methods of inhibiting RAS, including KRAS, HRAS and NRAS e.g., KRasG12C
  • a compound or a composition detailed herein sufficient to inhibit the activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), in said organism.
  • RAS including KRAS, HRAS and NRAS (e.g., KRasG12C)
  • NRAS e.g., KRasG12C
  • methods of inhibiting RAS, including KRAS, HRAS and NRAS e.g., KRasG12C
  • an amount of a compound or a composition detailed herein sufficient to inhibit the activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), in said animal.
  • RAS including KRAS, HRAS and NRAS (e.g., KRasG12C)
  • NRAS e.g., KRasG12C
  • methods of inhibiting RAS, including KRAS, HRAS and NRAS e.g., KRasG12C
  • a compound or a composition detailed herein sufficient to inhibit the activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), in said mammal.
  • provided herein are methods of inhibiting RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), activity in a human by contacting said human with an amount of a compound or a composition described herein sufficient to inhibit the activity of RAS, including KRAS, HRAS and NRAS (e.g., KRasG12C), in said human.
  • Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a RAS, including KRAS, HRAS and NRAS, mutation (e.g., a KRAS G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound or a composition described herein.
  • a compound or a composition as detailed herein for use in therapy is also provided herein.
  • a compound or a composition as detailed herein for use in the treatment of cancer are also provided herein.
  • a compound or a composition as detailed herein for use in the inhibition of RAS including KRAS, HRAS and NRAS.
  • a compound or a composition as detailed herein for use in the inhibition of KRAS is also provided herein.
  • a compound or a composition as detailed herein for use in the inhibition of KRAS G12C is also provided herein.
  • a compound or a composition as detailed herein for use in the treatment of a RAS-associated such KRAS-, HRAS- and NRAS-associated
  • a compound or a composition as detailed herein for use in the treatment of a KRAS-associated disease or disorder is also provided herein.
  • a compound or a composition as detailed herein for use in the treatment of a KRAS G12C-associated disease or disorder is also provided herein.
  • a compound or a composition as detailed herein in the manufacture of a medicament for the treatment of cancer is also provided herein.
  • a compound or a composition as detailed herein in the manufacture of a medicament for the inhibition of activity of RAS, including KRAS, HRAS and NRAS is also provided herein.
  • Also provided herein is the use of a compound or a composition as detailed herein in the manufacture of a medicament for the inhibition of activity of KRAS G12C.
  • a compound or a composition as detailed herein in the manufacture of a medicament for the treatment of a RAS-associated (such KRAS-, HRAS- and NRAS-associated) disease or disorder.
  • a compound or a composition as detailed herein in the manufacture of a medicament for the treatment of a KRAS- associated disease or disorder.
  • Also provided herein is the use of a compound or a composition as detailed herein in the manufacture of a medicament for the treatment of a KRAS G12C- associated disease or disorder.
  • compounds as detailed herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, and compositions as detailed herein, such as a pharmaceutical composition containing a compound provided herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient may be administered to an individual for treatment of a condition in combination with one or more additional pharmaceutical agents that can treat the condition.
  • an effective amount of a compound or a composition disclosed herein is administered to an individual for the treatment of a disease or disorder in combination with an additional therapeutic agent.
  • the compounds or compositions described herein may be co-administered with other anti- neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • other treatments such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • Also provided herein are methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound or a composition detailed herein.
  • such therapy includes but is not limited to the combination of a compound or a composition detailed herein with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
  • chemotherapeutics are presently known in the art and can be used in combination with the compounds or compositions described herein.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomeRASe inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and anti-androgens.
  • chemotherapeutic agents are described in WO 18/218070, which is incorporated herein by reference.
  • a method for using the compounds or compositions provided herein, in combination with radiation therapy for inhibiting abnormal cell growth or treating the hyperproliferative disorder in the individual is provided.
  • Techniques for administering radiation therapy are known in the art, and techniques can be used in the combination therapy described herein.
  • the administration of the compounds or compositions described herein in this combination therapy can be determined as described herein.
  • Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy.
  • brachytherapy refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site.
  • the term is intended without limitation to include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-53, Bi-212, P-32, and radioactive isotopes of Lu).
  • Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids.
  • the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, Ir- 192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays.
  • the radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198 and Y-90.
  • the radionuclide(s) can be embodied in a gel or radioactive micro spheres.
  • Many chemotherapeutics are presently known in the art and can be used in combination with the compounds or compositions described herein.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec ® (Imatinib Mesylate), Kyprolis ® (carfilzomib), Velcade ® (bortezomib), Casodex (bicalutamide), Iressa ® (gefitinib), Venclexta ® (venetoclax) and Adriamycin TM (doxorubicin) as well as a host of chemotherapeutic agents.
  • Gleevec ® Imatinib Mesylate
  • Kyprolis ® carfilzomib
  • Velcade ® bortezomib
  • Casodex bicalutamide
  • Iressa ® gefitinib
  • Venclexta ® venetoclax
  • Adriamycin TM doxorubicin
  • Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (Cytoxan TM ); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorocyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosure
  • anti-hormonal agents that act to regulate or inhibit hormone action on tumors
  • anti-estrogens including for example tamoxifen (Nolvadex TM ), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4- hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorel
  • anti-estrogens including for example tamoxif
  • the compounds or compositions described herein can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-Allylamino-17- demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Ca
  • the compounds or pharmaceutical compositions of the disclosure can be used in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors.
  • anti-angiogenesis agents examples include anti-neoplastic agents, and autophagy inhibitors.
  • a pharmaceutical composition provided herein is conjointly administered with a steroid.
  • Suitable steroids may include, but are not limited to, 21- acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide,
  • the compounds or compositions described herein can also be used in combination with additional pharmaceutically active agents that treat nausea.
  • agents that can be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or a pharmaceutically acceptable salt thereof.
  • the compounds or compositions described herein may also be used in combination with an additional pharmaceutically active compound that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways.
  • the additional pharmaceutically active compound is a PD-1 and PD-L1 antagonist.
  • the compounds or pharmaceutical compositions of the disclosure can also be used in combination with an amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune therapies, including monoclonal antibodies, immunomodulatory agents (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, anti- PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR- T cells, and BiTEs.
  • IiDs immunomodulatory agents
  • EGFR inhibitors examples include EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCl-1 inhibitors, BCL2-inhibitors, SHP inhibitors, proteasome inhibitors, and immune therapies, monoclonal antibodies, and immunomodulatory agents are described in WO 2019/241157, which is incorporated herein by reference.
  • the compound is included in the pharmaceutical composition in an amount sufficient to deliver to an individual a therapeutically effective amount without causing serious toxic effects in the patient treated.
  • the effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
  • Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight.
  • An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily. In some embodiments, the dosage will range from 0.01-3% wt/wt in a suitable carrier.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
  • a compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds or compositions described herein together with any of the dosages described herein.
  • a drug holiday e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more.
  • the present disclosure further provides articles of manufacture comprising a compound described herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, a composition described herein, such as a pharmaceutical composition containing a compound provided herein, or a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, or one or more unit dosages described herein in suitable packaging.
  • the article of manufacture is for use in any of the methods described herein.
  • kits for carrying out the methods of the present disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein or a salt thereof.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer.
  • Kits generally comprise suitable packaging.
  • kits may comprise one or more containers comprising a compound or a composition 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.
  • the kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease or disorder detailed herein 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).
  • 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 of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • General Synthetic Methods [0289]
  • the compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below).
  • a racemate may be separated using chiral High-Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the process of crystallization.
  • the resulting beta-ketoester is reacted with urea to give a quinazolindione intermediate that can be chlorinated using reagents such as POCl 3 .
  • Reaction of the chlorinated product with a piperazine derivative (appropriately protected) gives the 4-piperazino substituted adduct (Scheme 1).
  • Reductive amination can then be carried out in a single step or by isolating the intermediate enamine (Scheme 2).
  • the remaining chlorine on the heterocylic core is then displaced with a suitable nucleophile, typically using a Palladium-assisted reaction, followed by installation of the (substituted) acrylate by deprotection of the piperazine N-protecting group and acylation.
  • Scheme 3 An alternative sequence (Scheme 3) involves Pd-mediated substitution of the 2- chloro-tetrahydroquinazoline with a suitable nucleophile, followed by 2-step reductive amination, deprotection of the piperazine N-protecting group and acylation. [0296] Scheme 1
  • R A and R B are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl optionally contain 1-3 additional heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are optionally substituted by 1-5 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, -O-(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), -NH-C(O)(C 1 )
  • Embodiment 2 The compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R A and R B are taken together with the nitrogen atom to which they are attached to form a 9- to 10-membered heterocyclyl or 9- to 10-membered heteroaryl, wherein the 9- to 10-membered heterocyclyl and 9- to 10-membered heteroaryl optionally contain 1 additional nitrogen atom, and wherein the 9- to 10-membered heterocyclyl and 9- to 10-membered heteroaryl are optionally substituted by 1-2 groups independently selected from the group consisting of hydroxy, halo, cyano, oxo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -O-(C 1 -C 3 alkyl), -C(O)O(C 1 -C 3 alkyl), -NH-C(O)(C 1 -C 3 alkyl), and -NH-S(O) 2 (C 1
  • Embodiment 3 The compound of embodiment 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R A and R B are taken together with the nitrogen atom to which they are attached to form , , , , , , each of which is optionally substituted by -OH, F, Cl, Br, CN, oxo, -CH 3 , -CF 3 , -OCH 3 , -C(O)-OCH 3 , -NH-C(O)-CH 3 , or -NH-S(O) 2 -CH 3 .
  • X is -NR a R b , -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkylene)- (4- to 10-membered heterocyclyl), or -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and C 6 -C 10 aryl are optionally substituted by 1-5 R x groups; R a and R b are independently H, -C(O)(C 2 -C 6 alkenyl), 4- to 10-membered heterocyclyl, or - (C 1 -C
  • Embodiment 5 The compound of embodiment 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: X is -NR a R b ; R a and R b are independently H, -C(O)(C 2 -C 6 alkenyl), 4- to 10-membered heterocyclyl, or - (C 1 -C 6 alkylene)-C(O)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and is optionally substituted by 1-5 R x groups, or R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-5 R x groups;
  • Embodiment 6 The compound of embodiment 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R a and R b are independently H, -C(O)(C 2 -C 3 alkenyl), 6-membered heterocyclyl, or -(C 1 -C 6 alkylene)-C(O)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), wherein the 6-membered heterocyclyl contains 1 nitrogen atom, and is optionally substituted by 1 R x group; and R x is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), or C(O)O(C 1 - C 4 alkyl).
  • R a and R b are independently H, -C(O)(C 2 -C 3 alkenyl), 6-membered heterocyclyl, or -(
  • Embodiment 7 The compound of embodiment 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R a and R b are taken together with the nitrogen atom to which they are attached to form a 4- to 6- membered heterocyclyl optionally containing one additional nitrogen atom, and wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1-3 R x groups; and each R x is independently C 1 -C 3 alkyl, -NH 2 , -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkyl), -C(O)N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), oxo, or 6-membered heterocyclyl optionally substituted by C 1 -C 3 alkyl.
  • Embodiment 8 The compound of embodiment 7, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R a and R b are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperazinyl, each of which is optionally substituted by 1-3 R x groups.
  • X is -O-(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkylene)-(4- to 10-membered heterocyclyl), or -O-(C 1 -C 6 alkylene)-(C 6 -C 10 aryl), wherein the 4- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl and C 6 -C 10 aryl are optionally substituted by 1-5 R x groups, and each R x is independently C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-NH 2 , -
  • Embodiment 10 The compound of embodiment 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: X is -O-(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkylene)-(5- to 6- membered heterocyclyl), or -O-(C 1 -C 3 alkylene)-(phenyl), wherein the 5- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from the group consisting of N and O, and wherein the 5- to 6-membered heterocyclyl and phenyl are optionally substituted by 1-3 R x groups, and each R x is independently C 1 -C 3 alkyl, -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), -(C 1 -C 3 alkylene)-NH 2 , -NH 2 , or -O
  • Embodiment 11 The compound of embodiment 10, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heterocyclyl is pyrrolidinyl or morpholinyl.
  • Embodiment 12 The compound of any one of embodiments 1-11, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R 1 is H.
  • Embodiment 13 The compound of any one of embodiments 1-11, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R 1 is Embodiment 14.
  • Embodiment 17 A compound selected from the group consisting of the compounds in Table 1, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • Embodiment 18 A pharmaceutical composition comprising a compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.
  • Embodiment 19 A method of treating a disease mediated by KRAS in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 18.
  • Embodiment 20 The method of embodiment 19, wherein the disease is cancer.
  • Embodiment 21 The method of embodiment 20, wherein the cancer is a cancer associated with mutations, activation, or involvement of the Ras pathway.
  • Embodiment 22 The method of embodiment 21, wherein the Ras pathway is associated with or dependent on G12C mutant RAS.
  • Embodiment 23 The method of embodiment 20, wherein the cancer is non-small cell lung cancer or pancreatic cancer.
  • Embodiment 24 A method of inhibiting KRAS in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 18.
  • Embodiment 25 A compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in therapy.
  • Embodiment 26 A compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by KRAS.
  • Embodiment 27 A compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by KRAS.
  • Embodiment 28 A method of treating a disease mediated by RAS in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 18.
  • Embodiment 29 The method of embodiment 28, wherein the disease is cancer.
  • Embodiment 30 The method of embodiment 29, wherein the cancer is a cancer associated with mutations, activation, or involvement of the Ras pathway.
  • Embodiment 31 The method of embodiment 30, wherein the Ras pathway is associated with or dependent on G12C mutant RAS.
  • Embodiment 32 A method of treating a disease mediated by RAS in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 18.
  • Embodiment 29 The method of embodiment 28, wherein the disease is cancer.
  • Embodiment 30 The method of embodiment 29, wherein the cancer is a cancer associated
  • Embodiment 33 A method of inhibiting RAS in a cell, comprising contacting the cell with a therapeutically effective amount of the compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 18.
  • Embodiment 34 A compound of embodiment 1, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by RAS.
  • the reaction was quenched with sat. aq. NH 4 Cl solution (10 mL), diluted with water (200 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure.
  • Step A To a solution of benzyl (S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2- (cyanomethyl)piperazine-1-carboxylate (Intermediate 30, 7 g, 15.9 mmol) and 1,2,3,4- tetrahydroquinoline (2.75 g, 20.7 mmol) in dry toluene (100 mL) was added PTSA (547.6 mg, 3.2 mmol) at rt. The reaction solution was heated to 60 °C and stirred for 16 hours under a N 2 atmosphere. The reaction was concentrated under vacuum.
  • the reaction mixture was stirred at 0 °C for 0.5 h.
  • the mixture was diluted with water and extracted with DCM (20 mL x 3).
  • the combined organic layers were dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure.
  • Examples S04 to S135 were prepared by procedures similar to the ones described in Example S01, S02, and S03, using the amine (or protected amine) corresponding to column R Q in Example S01, Step A and either the amine or alcohol corresponding to column X in Example S01, Step C with the designated reagents, wherein the compounds are represented by the general structure below and wherein R Q corresponds to the –N(R A )(R B ) moiety of the compound of formula (I’):
  • the resulting product of a reaction is a mixture of isomers (e.g., mixture of diastereomers)
  • the mixture can be separated into individual stereoisomers by known methods (e.g., HPLC or SFC) as, for example, described in Example 2 and 3.
  • HPLC or SFC e.g., HPLC or SFC
  • the configuration of the resultant individual stereoisomers is arbitrarily assigned.
  • the absolute configuration of the stereoisomers e.g., the specific compound associated with the corresponding 1H NMR data, may be obtained by known methods. For example, Examples S02 and S03 are recognized as a pair of diastereomers.
  • Examples S162 to S170 were prepared by procedures similar to the ones described in Example S01, S02, and S03, using the amine (or protected amine) corresponding to column R Q in Example S01, Step A and either the amine or alcohol corresponding to column X in Example S01, Step C and replacing benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate in Example S01 Step E with the designated reagents, wherein the compounds are represented by the general structure below and wherein R Q corresponds to the –N(R A )(R B ) moiety of the compound of formula (I’):
  • Step A A mixture of benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydroquinazolin-4-yl)piperazine-1- carboxylate (1.4 g, 2.15 mmol), 8-chloro-1,2,3,4-tetrahydroquinoline (0.54 g, 3.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 , 192 mg, 0.21 mmol), Cs 2 CO 3 (2.1 g, 6.45 mmol) and tBu 3 P (10 % in toluene; 869 mg, 0.43 mmol) in dry toluene (50 mL) was degassed and purged with N 2 three times.
  • Step A A mixture of benzyl (S)-2-(cyanomethyl)-4-(2-(3-(dimethylamino)azetidin-1-yl)-7- (((trifluoromethyl)sulfonyl)oxy)-5,6-dihydroquinazolin-4-yl)piperazine-1-carboxylate (1 g, 1.57 mmol), 8-chloro-1,2,3,4-tetrahydroquinoline (0.4 g, 2.36 mmol), 8-chloro-1,2,3,4- tetrahydroquinolinetris (393 mg, 2.35 mmol), (dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 , 143.6 mg, 0.16 mmol), Cs 2 CO 3 (1.5 g, 4.71 mmol) and tBu 3 P (10 % in toluene; 646 mg, 0.32 mmol) in dry toluene (40
  • Step B To the suspension of benzyl (S)-4-(7-(8-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-(3- (dimethylamino)azetidin-1-yl)-5,6-dihydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1- carboxylate (0.37 g, 0.57 mmol) in HOAc (5 mL) was added NaBH 4 (108 mg, 2.84 mmol ) in portions and the reaction mixture was stirred at rt for 30 mins. Then the mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2).
  • Step A A mixture of benzyl (S)-2-(cyanomethyl)-4-(2-(3-(dimethylamino)azetidin-1-yl)-7- (((trifluoromethyl)sulfonyl)oxy)-5,6-dihydroquinazolin-4-yl)piperazine-1-carboxylate ( 330 mg, 0.52 mmol), 3,7-difluoro-1,2,3,4-tetrahydroquinoline (132 mg, 0.78 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 , 48 mg, 0.05 mmol), Cs 2 CO 3 (508 mg, 1.56 mmol) and tBu 3 P (10 % in toluene; 210 mg, 0.1 mmol) in dry toluene (4 mL) was degassed and purged with N 2 three times.
  • Examples S192 to S212 were also prepared by procedures similar to the ones described herein, using the amine (or protected amine) corresponding to column R Q and replacing either the amine or alcohol corresponding to column X with the designated reagents, wherein the compounds are represented by the general structure below and wherein R Q corresponds to the –N(R A )(R B ) moiety of the compound of formula (I’):
  • Step A A mixture of benzyl (S)-4-((R)-2-chloro-7-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)- 5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (400 mg, 0.697 mmol), trans-4-methoxy-1-methylpyrrolidin-3-ol (120 mg, 0.92 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 , 64 mg, 0.07 mmol), Cs 2 CO 3 (469 mg, 1.44 mmol) and Ruphos (65 mg, 0.014 mmol) in dry toluene (8 mL) was degassed and purged with N 2 three times.
  • Example S222 was prepared by using a procedure similar to the on described in Example S219, using 4-methoxy-N-methylpyrrolidin-3-amine in Step A and proceeding to Step C using the slower eluting isomer P2 obtained in Step B.

Abstract

La présente divulgation concerne de manière générale des composés et des compositions de ceux-ci pour l'inhibition de RAS, tel que KRAS, HRAS et NRAS, y compris des formes mutantes de KRAS, HRAS et NRAS, en particulier ceux présentant une mutation G12C, des procédés de préparation desdits composés et desdites compositions, et leur utilisation dans le traitement ou la prophylaxie de divers cancers, tels que le cancer du poumon, le cancer colorectal, le cancer du pancréas, le cancer de la vésicule biliaire, le cancer de la thyroïde et le cancer des voies biliaires.
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