[go: up one dir, main page]

WO2025171055A1 - Conjugués hétérocycliques et leurs utilisations - Google Patents

Conjugués hétérocycliques et leurs utilisations

Info

Publication number
WO2025171055A1
WO2025171055A1 PCT/US2025/014660 US2025014660W WO2025171055A1 WO 2025171055 A1 WO2025171055 A1 WO 2025171055A1 US 2025014660 W US2025014660 W US 2025014660W WO 2025171055 A1 WO2025171055 A1 WO 2025171055A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
membered
conjugate
carbocycle
membered heterocycle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014660
Other languages
English (en)
Inventor
Yi Liu
Pingda Ren
Baogen Wu
Rasmus Hansen
Matthew R. Janes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kumquat Biosciences Inc
Original Assignee
Kumquat Biosciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kumquat Biosciences Inc filed Critical Kumquat Biosciences Inc
Publication of WO2025171055A1 publication Critical patent/WO2025171055A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell

Definitions

  • Cancer e.g., tumor, neoplasm, metastases
  • K-Ras Kirsten Ras oncogene
  • PDAC pancreatic ductal adenocarcinoma
  • Ras proteins have long been considered “undruggable,” due to, in part, high affinity to their substrate guanosine-5'-triphosphate (GTP) and/or their smooth surfaces without any obvious targeting region.
  • GTP guanosine-5'-triphosphate
  • the specific G12C Ras gene mutation has been identified as a druggable target to which a number of G12C specific inhibitors have been developed.
  • such therapeutics are still of limited application, as the G12C mutation in Ras exhibits a much lower prevalence rate as compared to other known Ras mutations, such as G12D and G12V. Drug resistance and lack of durability impose further limitations to such therapeutics.
  • KRas inhibitors including pan KRas inhibitors capable of inhibiting two or more KRas mutants and/or wildtype KRas within this given Ras isoform (e.g., inhibitors targeting mutant KRas proteins such as KRas G12D, G12C, G12S, G13D, and/or G12V, for the treatment of Ras-associated diseases (e.g., cancer).
  • compositions and methods can be particularly useful for treating a variety of diseases including, but not limited to, cancers and neoplasia conditions.
  • the present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and/or treatment for a wide diversity of diseases.
  • the present disclosure provides a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the antigen binding unit and the KRAS inhibitor in the conjugate synergistically inhibits signaling output of the first antigen or KRAS.
  • the conjugate provided herein comprises an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to the small-molecule KRAS inhibitor through a chemical linker.
  • the present disclosure provides a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the antigen binding unit and the KRAS inhibitor in the conjugate synergistically inhibits signaling output of the first antigen and KRAS.
  • the KRAS inhibitor is characterized by a PAMPA permeability (P e ) less than 1 x 10 -6 cm/s.
  • the conjugate is characterized by an increased concentration of the KRAS inhibitor in tumor tissue relative to plasma as ascertained by the formula: ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t-k /[KRASi] p-k ) > 1, wherein [KRASi] t-c is concentration of the KRAS inhibitor in tumor tissue at a first time -point following administration of the conjugate; wherein [KRASi] p-c is plasma concentration of the KRAS inhibitor at the same time-point following the administration of the conjugate; wherein [KRASi] t-k is concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point; and wherein [KRASi] p-k is plasma concentration of the KRAS inhibitor at the same time -point following the administration of the KRAS inhibitor alone at the equivalent dose.
  • AgB is an antigen binding unit
  • the linker comprises one or more components selected from Val-Cit, Glu-Val-Cit, Val-Ala, Val- Val, Val-Gly, Gly-Gly, Gly-Cit, Glu-Gly-Cit, Ala-Ala-Asn, Ala-Gly-Ala, Ala-Pro, Ala-Ser, and Phe-Lys.
  • p is selected from 2 to 8.
  • q is selected from 1 to 4.
  • D is a small-molecule KRAS inhibitor.
  • Z is selected from O, N, C(R 5 ) 2 , C(O), S, S(O), and S(O) 2 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and -OH;
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.
  • the compound of Formula (I) is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle).
  • A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, such as A is pyridinyl.
  • R 11 is hydrogen.
  • R 10 is selected from hydrogen and halogen; or R 9 and R 10 , together with the atoms to which they are attached, form C 4-8 carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted.
  • R 10 is hydrogen.
  • R 9 is optionally substituted
  • C 1-3 alkyl such as R 9 is CH 3 .
  • R 4 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more R 20 .
  • R 4 is selected from C 1-6 alkyl and -C 0-6 alkyl-(3- to 12- membered heterocycle), each of which is optionally substituted with one or more substituents independently selected from halogen, -CH 3 , -NH 2 , -NHCH 3 , and -N(CH 3 ) 2 -
  • R 7 is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four R 20 .
  • R 7 is benzothiophenyl optionally substituted with one, two, three, or four R 20 .
  • X is C(R 6 );
  • A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, - C 3-8 carbocycle, 3- to 8-membered heterocycle, -OR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -N(R 12 )C(O)N(R 12 )(R 13 ), -C(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), and -N(R 12 )C(O)R 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 3-8 carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R 20 ; wherein two R 3 are optionally taken together with the atom or atoms to which they are attached to form C
  • R 7 is benzo [b]thiophen-4-yl optionally substituted with one, two, three, or four R 20 ;
  • R 9 is C 1-3 alkyl optionally substituted with one, two, or three R 20 ;
  • R 10 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, 3- to 8- membered heterocycle, -OR 22 , -N(R 22 )(R 23 ), -C(O)OR 22 , -N(R 22 )C(O)N(R 22 )(R 23 ), -C(O)R 22 , -OC(O)R 22 , - C(O)N(R 22 )(R 23 ), and -N(R 22 )C(O)R 22 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 3-8 carbocycle, and 3- to 8- membered heterocycle are optionally substituted with one, two, or three substituents independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl
  • R 2 is selected from hydrogen
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 .
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the conjugate described herein, or a salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a conjugate described herein, or a salt thereof.
  • the present disclosure provides a method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a conjugate described herein, or a salt thereof.
  • the cancer of a method described herein may be a solid tumor or a hematological cancer.
  • the cancer comprises a wildtype K-Ras or a mutant K-Ras including but not limited to K-Ras G12C, G12D, G12S, or G12V mutant protein.
  • the present disclosure provides a method of reducing plasma concentration of a small-molecule KRAS inhibitor, comprising providing a conjugate described herein to a subject, wherein reduced plasma concentration is ascertained by the formula: [KRASi] p-c /[KRASi] p-k ⁇ 1 , wherein [KRASi] p-c is plasma concentration of the KRAS inhibitor at a first time -point following administration of the conjugate; and wherein [KRASi] p-k is plasma concentration of the KRAS inhibitor following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point.
  • the present disclosure provides a method of increasing concentration of a small-molecule KRAS inhibitor in tumor tissue, comprising providing a conjugate described herein to a subject, wherein increased tumor tissue concentration is ascertained by the formula: ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t .
  • [KRASi] t-c is concentration of the KRAS inhibitor in tumor tissue at a first time-point following administration of the conjugate; wherein [KRASi] p-c is plasma concentration of the KRAS inhibitor at the same time-point following the administration of the conjugate; wherein [KRASi] t-k is concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time -point; and wherein [KRASi] p-k is plasma concentration of the KRAS inhibitor at the same time -point following the administration of the KRAS inhibitor alone at the equivalent dose.
  • efficacy of the conjugate may be greater than efficacy of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration. In some embodiments, toxicity of the conjugate is less than toxicity of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration.
  • FIG. 1 depicts a sequence alignment of various wild type Ras proteins including K-Ras, H-Ras, N-Ras, RalA, and RalB, from top to bottom.
  • C x-y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl, is meant to include groups that contain from x to y carbons in the chain.
  • C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups, that contain from x to y carbons in the chain.
  • Alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups.
  • An alkyl group may contain from one to twelve carbon atoms (e.g., C 1-12 alkyl), such as one to eight carbon atoms (C 1-8 alkyl) or one to six carbon atoms (C 1-6 alkyl).
  • alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl.
  • An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • alkenyl refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenyl groups, containing at least one double bond.
  • An alkenyl group may contain from two to twelve carbon atoms (e.g., C 2-12 alkenyl), such as two to eight carbon atoms (C 2-8 alkenyl) or two to six carbon atoms (C 2-6 alkenyl).
  • Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-l -enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Alkylene or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., C 1-12 alkylene), such as one to eight carbon atoms (C 1-8 alkylene) or one to six carbon atoms (C 1-6 alkylene).
  • Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene.
  • alkenylene and alkynylene refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively.
  • alkylene, alkenylene or alkynylene chain can be through one carbon or any two carbons of the chain.
  • an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.
  • Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain.
  • a heteroalkyl, hetero alkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Hetero alkylene refers to substituted or unsubstituted alkylene, alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8- membered hetero alkylene group has a chain length of 3 to 8 atoms.
  • the points of attachment of the heteroalkylene, hetero alkenylene or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, hetero alkenylene or heteroalkynylene chain.
  • a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.
  • Heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, for example 1, 2, 3, or 4 heteroatoms selected from O, S, P, and N. Heterocycle may include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
  • a heterocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof.
  • a heterocycle e.g., pyridyl
  • a polycyclic heteroaryl contains a number or rings equal to the minimum number of scissions required to convert the heteroaryl into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.).
  • the heteroatom(s) in the heteroaryl may optionally be oxidized.
  • One or more nitrogen atoms, if present, are optionally quatemized.
  • the heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • a waved line drawn across or at the end of a bond or a dashed bond are used interchangeably herein to denote where a bond disconnection or attachment occurs.
  • R7 is 2-fluoro-6-hydroxyphenyl as in then R 7 may be depicted as
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • an “optionally substituted” group may be either unsubstituted or substituted.
  • stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.
  • a mutant Ras may comprise about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, a mutant Ras may comprise up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations.
  • the small molecule has a molecular weight of 100 to 1000 Da, such as 100 to 900 Da, 100 to 850 Da, 100 to 800 Da, 100 to 750 Da, 100 to 700 Da, 100 to 650 Da, 100 to 600 Da, 100 to 550 Da, 100 to 500 Da, 150 to 900 Da, 150 to 850 Da, 150 to 800 Da,
  • ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t-k /[KRASi] p-k ) is greater than 1.1, such as greater than 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50. In some embodiments, ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t-k /[KRASi] p-k ) is greater than 2.
  • AgB is an antigen binding unit
  • the conjugate of Formula (A) is selected from:
  • an antigen binding unit is bivalent and mono-specific (i.e., having two binding domains that specifically bind to the same antigen). In embodiments in which an antigen binding unit is trivalent or greater, the antigen binding unit is typically bi-specific or greater. Antigen binding units having a third binding domain attached to the C-terminal end of a light chain and/or the C-terminal end of an Fc domain can be bi-specific, tri-specific or multi-specific.
  • a linker containing such a protease cleavage site may further comprise one or more components selected from pentafluorophenyl, succinimide, maleimide, and para-aminobenzoic acid (PABA).
  • the linker is a compound of the formula: (maleimidocaproyl)-(protease cleavage site)-(para-aminobenzyloxycarbonyl).
  • the linker may comprise a maleimide at one end and a protease cleavage site at the other end.
  • the linker comprises a peptide, such as a dipeptide, tripeptide, or tetrapeptide.
  • the peptide may comprise natural amino acids, unnatural amino acids, or combinations thereof.
  • the peptide comprises L-amino acids.
  • a linker may be polyvalent such that it covalently links more than one KRAS inhibitor to a single site on the antigen binding unit, or monovalent such that it covalently links a single KRAS inhibitor to a single site of the antigen binding unit.
  • Exemplary polyvalent linkers that may be used to attach two or more KRAS inhibitors to an antigen binding unit of the conjugate include Fleximer® linkers.
  • a Fleximer® linker utilizes a solubilizing poly acetal backbone to incorporate two or more KRAS inhibitors (D) via a sequence of ester bonds, for example, utilizing a linker comprising two or more units of the structure shown below. This methodology can render highly- loaded conjugates (e.g., DAR20 — conjugates of Formula (A) wherein q is 20).
  • R 1 is a reactive group
  • L 1 is a bridging spacer
  • Lp is a bivalent peptide spacer
  • G-L 2 -A is a self-immolative spacer
  • R 2 is a hydrophilic moiety
  • L 2 is a bond, a methylene, a neopentylene or a C 2 -C3alkenylene
  • conjugate or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the conjugate includes a structure represented by formula (Xc):
  • the benzene ring of L3 can be substituted with the optionally substituted structural unit -X.
  • the structural unit -X can include optionally substituted wherein X 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, linear heteroalkyl comprising 1-8 atoms, and linear-cyclic heteroalkyl comprising 1-8 atoms, where the heteroalkyl comprises 1-3 atoms selected from N, O or S, and the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, linear heteroalkyl comprising 1-8 atoms, and linear-cyclic heteroalkyl comprising 1 -8 atoms are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, amino, alkyl, carboxy, alkoxy, or cycl
  • the conjugate is a conjugate described in WO2013/173337, which is incorporated herein in its entirety.
  • the conjugate is represented by Formula Xd: or a salt thereof (e.g., pharmaceutically acceptable salts);
  • L is a antigen binding unit;
  • D' is a KRAS inhibitor;
  • L° is the optional secondary linker assembly;
  • L ss is the self-stabilizing linker assembly, wherein M 1 is a succinimide ring or a hydrolyzed succinamide or together with BU forms a dilactam;
  • BU is a Basic unit;
  • HE is a hydrolysis enhancer comprising an electron withdrawing group;
  • the circle represents a scaffold that can be C 1-8 alkylene, Ci.
  • the scaffold is Ci alkylene or C 1 -
  • M 1 represents a succinimide ring or a hydrolyzed succinamide ring or a dilactam formed when the base reacts with the succinimide ring
  • BU is a Basic unit
  • HE is a hydrolysis enhancer comprising an electron withdrawing group
  • the circle represents a scaffold that can be C 1-8 alkylene, C 1-8 heteroalkyiene, C 6-10 arylene, or C 4- 10 heteroarylene, and optionally comprises a reactive site suitable for attachment to the optional secondary linker assembly, D !
  • the scaffold is C 1-3 alkylene or C 1-3 heteroalkyiene.
  • the alkylene is a straight chain or branched alkylene.
  • the circle represents a scaffold that is C1, C2, C3. or C4 straight or branched chain alkylene, r is zero, and the sum of m+q is 1.
  • the circle represents a scaffold that is C1, C2, C3. or C4 straight or branched chain alkylene, and m and r are zero.
  • m is 1 , and q and r are 0; 2) q is 1 , and m and r are 0; 3) r is 1 , and m and q are 0; 4) m is 1 , q and r are 0, and a is 1 ; 5) q is 1 , m and r are 0, and a is 1 ; 6) r is 1 , m and q are 0, and a is 1 ; 7) m is 1 , q and r are 0, and D' is a KRAS inhibitor; 8) q is 1.
  • n and r are 0, and D' is a KRAS inhibitor; 9) r is 1 , m and q are 0, and D' is a KRAS inhibitor, D; 10) m is 3 , q and r are 0, a is 1, and D : is a Drug unit, D: 11) q is 1, m and r are 0, a is 1, and D' is a KRAS inhibitor; or 12) r is 1 , m and q are 0, a is 1 , and D' is a KRAS inhibitor.
  • the Basic unit comprises a primary, a secondary amine, or a tertiary amine.
  • the Basic unit is selected from the group consisting of-(C(R 9 )( R 10 )) x NH 2 , -(C(R 9 )( R 10 )) x NHR a , and -(C(R 9 )( R 10 )) x NR a 2 , wherein x is an integer of from 0-4 (or from 1 to 4) and each R a is independently selected from the group consisting of C 1-6 alkyl and C 1- 6 haloalkyl, or two R a groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group, provided that if x is zero there are no less than 2 intervening atoms between the base of the Basic unit and the nitrogen atom of the succinimide
  • x is an integer of from 1 to 4.
  • the Basic unit is NH 2 -CH 2 NH 2 , -CH 2 CH 2 NH 2 , - CH 2 CH 2 CH 2 NH2, or -CH 2 CH 2 CH 2 CH 2 NH 2 provided that if the Basic unit is -NH 2 , there are no less than 2 intervening atoms between the base and the nitrogen atom of the succinimide (hydrolyzed or non-hydrolyzed) or dilactam.
  • the conjugate is a conjugate described in W02010/093395, which is incorporated herein in its entirety.
  • the conjugate may have the formula Xe, MAb-[L2]-[L l]-[AA] m - [A']-D; where MAb is a disease -targeting antibody; L2 is a component of the cross-linker comprising an antibodycoupling moiety and one or more of acetylene (or azide) groups; L 1 comprises a defined PEG with azide (or acetylene) at one end, complementary to the acetylene (or azide) moiety in L2, and a reactive group such as carboxylic acid or hydroxyl group at the other end; AA is an L-amino acid; m is an integer with values of 0, 1, 2, 3, or 4; and A' is an additional spacer, selected from the group of ethanolamine, 4-hydroxybenzyl alcohol, 4- aminobenzyl alcohol, or substituted or unsubstituted
  • the L amino acids of 'AA' are selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. If the A' group contains hydroxyl, it is linked to the hydroxyl group or amino group of D in the form of a carbonate or carbamate, respectively.
  • A' is a substituted ethanolamine derived from an L-amino acid, wherein the carboxylic acid group of the amino acid is replaced by a hydroxymethyl moiety.
  • A' may be derived from any one of the following L-amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • the conjugate is a conjugate described in WO2019081455, which is incorporated herein in its entirety.
  • the conjugate may have the formula Xf wherein D is KRAS inhibitor, X is an optional cleavable moiety for releasing D, Z is an optional spacer, and a is 1 or more, b is 1 or more and m is 1 or more; L is an orthogonal connector that allows for (HP SMW ) to be in an orthogonal orientation with respect to (X-D), HP SMW results from covalent binding to said orthogonal connector L, of a single molecular weight homopolymer having formula (Xfb) wherein n is one or more; R 1 and R 2 are different, and one of R 1 and R 2 is H or an inert group, the other one of R 1 and R 2 being a functionalized reactive group, said group being reactive for covalently binding a bindable group, in such reaction conditions that the inert group is non-reactive, Z 1 and Z 2 ,
  • k is an integer which is at least 2, it is preferably 100 at most, more preferably 50 at most, and specifically 2-30, and more specifically 2-24, 6-24, or 12-24.
  • said functionalized reactive group R 1 or R 2 may be selected from the following groups: carboxylic acid group, amino groups NRR" wherein R and R" are independently selected from H, (C 1 -C 6 ) alkyl optionally interrupted by at least one heteroatom selected among O, N and S, hydroxyl group, halogen atoms, hydrazine (-NH 2 - NH 2 ) group, nitro group, hydroxylamine group, azido group, (C 2 -C 6 ) alkynyl group, (C 2 -C 6 ) alkenyl group, thiol group, activated ester groups such as N-hydroxysuccinimide ester, perfluorinated esters, nitrophenyl esters, azabenzotriazole and benzotriazole activated esters, acylureas, boronic acid B(OR"") 2 groups, wherein R"" is a hydrogen atom or a C 1 -C 6 alkyl group, thio
  • the conjugate of formula Xf is wherein R 6 is —C 1 -C 10 alkylene-, — C 1 -C 10 heteroalkylene-, -C 3 -C 8 carbocyclo-, -O-
  • the linker comprises one or more components independently selected from polyethylene glycol, polysarcosine, a hydrazone, acetal, maleimide, succinimide, asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, valine, alanine, glycine, leucine, isoleucine, methionine, tryptophan, proline, histidine, citrulline, phenylalanine, carboxylate, p-aminobenzyloxy carbonyl, alkyl, alkene, alkyne, aryl, cycloalkyl, heterocycle, glycoside, silyl ether, hydroxy, ether, ketone, ester, carbonate, amide, urea, carbamate, sulfide, disulfide, sulfate, sulfonamide,
  • the linker is a compound of the formula: wherein: indicates an attachment site to the antigen binding unit;
  • Z 1 is a product formed by reaction of the antigen binding unit with a reactive precursor of Z 1 ;
  • Z 2 is absent or an optionally substituted spacer comprising one or more components independently selected from C 1-6 alkyl, (CH 2 CH 2 O) n2 , and -C(O)NH-, or any combination thereof;
  • Z 3 is selected from Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu- Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala-Vai, Val-Val, Val-Gly, Gly-Val, Phe-Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg- Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu- Val-C
  • R z is selected from hydrogen, -C 1-4 alkyl-O n3 -(C 1-4 alkylene) n4 -Z 4 , -C 1-4 alkyl-N-[(C 1-4 alkylene)-Z 4 ] 2 , -C 2-4 alkynyl-C 1-4 alkyl-O n3 -(C 1-4 alkylene) n4 -Z 4 , and -C 2-4 alkynyl-C 1-4 alkyl-N-[(C 1-4 alkylene)-Z 4 ] 2 ;
  • Z 4 is selected from -SO 3 H, -CO 2 H, PEG 4-32, and a sugar moiety; n1, n3, and n4 are each independently 0 or 1 ; n2 is an integer from 1 to 6; and indicates an attachment site to the KRAS inhibitor.
  • the linker is a compound of the formula: wherein: indicates an attachment site to the antigen binding unit;
  • Z 1 is a product formed by reaction of the antigen binding unit with a reactive precursor of Z 1 ;
  • Z 2 is absent or an optionally substituted spacer comprising one or more components independently selected from C 1-6 alkyl, (CH 2 CH 2 O) n2 . -C(O)NH-, -C(O)NCH 3 -, (C(O)CH 2 N(CH 3 )) n2 , or any combination thereof;
  • Z 3 is selected from a bond, Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu- Vai, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala- Vai, Val-Val, Val-Gly, Gly-Val, Phe- Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu-
  • R z is selected from hydrogen, Z 4 , -C 1-4 alkyl-O n3 -(C 1-4 alkylene) n4 -Z 4 , -C 1-4 alkyl-N-[(C 1-4 alkylene)-Z 4 ] 2 , - C 2-4 alkynyl-C 1-4 alkyl-O n3 -(C 1-4 alkylene) n4 -Z 4 , and -C 2-4 alkynyl-C 1-4 alkyl-N-[(C 1-4 alkylene)-Z 4 ] 2 ;
  • Z 4 is selected from -SO 3 H, -CO 2 H, PEG 4-32, -(CH 2 N(CH 3 )C(O)) n2 CH 3 , and a sugar moiety; n1, n3, and n4 are each independently 0 or 1 : n2 is an integer from 1 to 20: and indicates an attachment site to the KRAS inhibitor.
  • a conjugate of the present disclosure comprises a linker selected from:
  • a conjugate of the present disclosure comprises a linker selected from:
  • the linker is a compound of the formula: wherein: indicates an attachment site to the antigen binding unit;
  • Z 1 is a product formed by reaction of the antigen binding unit with a reactive precursor of Z 1 ;
  • Z 2 is absent, C 1-6 alkyl, (CH 2 CH 2 O) n2 . -C(O)NH-, -C(O)NCH 3 -, (C(O)CH 2 N(CH 3 )) n2 , - ((CH 2 CH 2 O) n2 (CH 2 CH 2 )C(O))N(CH 2 C(O)N(CH 3 )-(CH 2 CH 2 O) n2 -(CH 2 CH 2 N(CH 3 )-(C(O)CH 2 N(CH 3 )) n2 - C(O)CH 3 )CH 2 -, -(C 1-6 alkyl)C(O)N(CH 2 C(O)N(CH 3 )-(CH 2 CH 2 O) n2 -(CH 2 CH 2 N(CH 3 )-(C(O)CH 2 N(CH 3 )) n2 - C(O)CH 3 )CH 2 -, -(C 1-6 alkyl
  • Z 3 is selected from a bond, Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu-Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala- Vai, Vai- Vai, Val-Gly, Gly-Val, Phe- Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu
  • R z is selected from hydrogen, -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 CH 3 , -CH 2 N(CH 3 )(C(O)CH 2 N(CH 3 )) n2 - C(O)CH 3 , -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 -CH 2 CH 2 C(O)-(N(CH 3 )CH 2 C(O)) n2 -N(CH 3 ) 2 , -SO 3 H, -CO 2 H, PEG 4-32, polysarcosine, -(CH 2 N(CH 3 )C(O)) n2 CH 3 , and a sugar moiety; n3, and n4 are each independently 0 or 1 ; n2 is independently an integer from 1 to 20; and indicates an attachment site to the KRAS inhibitor.
  • Z 1a is a moiety capable of forming a covalent bond with an antigen binding unit
  • R z is selected from hydrogen, Z 4 , -C 1-4 alkyl-O n3 -(C 1-4 alkylene) n4 -Z 4 , -C 1-4 alkyl-N-[(C 1-4 alkylene)-Z 4 ] 2 , - C 2-4 alkynyl-C 1-4 alkyl-O n3 -(C 1-4 alkylene) n4 -Z 4 , and -C 2-4 alkynyl-C 1-4 alkyl-N-[(C 1-4 alkylene)-Z 4 ] 2 ;
  • R z is selected from hydrogen, -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 CH 3 , -CH 2 N(CH 3 )(C(O)CH 2 N(CH 3 )) n2 - C(O)CH 3 , -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 -CH 2 CH 2 C(O)-(N(CH 3 )CH 2 C(O)) n2 -N(CH 3 ) 2 , -SO 3 H, -CO 2 H, PEG 4-32, polysarcosine, -(CH 2 N(CH 3 )C(O)) n2 CH 3 , and a sugar moiety; nl, n3, and n4 are each independently 0 or 1 ; n2 is independently an integer from 1 to 20; and the KRAS inhibitor is optionally a compound of Formula (I), (I-a), (I-b), (I-
  • a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X is selected from N and C(R 6 );
  • R 2 , R 5 , R 6 , and R 8 are each independently selected at each occurrence from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3 -i 2 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , - N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 4 is selected from hydrogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR 12 , -C(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O) 2 R 12 , - S(O)(NR 12 )R 12 , -S(O) 2 N(R
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted; m is 0, 1, 2, or 3; n is 1 or 2;
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.
  • the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.
  • the compound of Formula (I) has the formula: wherein all variables are as described for Formula (I).
  • a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X is selected from N and C(R 6 );
  • Z is selected from O, N, C(R 5 ) 2 , C(O), S, S(O), and S(O) 2 ;
  • R 2 , R 5 , R 6 , and R 8 are each independently selected at each occurrence from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , - N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 4 is selected from hydrogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR 12 , -C(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O) 2 R 12 , - S(O)(NR 12 )R 12 , -S(O) 2 N(R
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R 20 ; m is 0, 1, 2, or 3; n is 1 or 2;
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and -OH;
  • R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle); and
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.
  • the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.
  • Formula (I) has the formula: wherein all variables are as described for Formula (I).
  • the KRAS inhibitor for generating a conjugate is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X is selected from N and C(R 6 );
  • Z is selected from O, N, C(R 5 ) 2 , C(O), S, S(O), and S(O) 2 ;
  • A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms
  • R 2 , R 5 , R 8 , R 9 , and R 10 are each independently selected at each occurrence from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 6 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -SF 5 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), - N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R 20 ; m is 0, 1, 2, or 3; n is 1 or 2;
  • R 11 is selected from hydrogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)OR 12 , -C(O)OC(O)R 12 , -C(O)O-(C 1-6 alkyl)-OR 15 , -(C 1-6 alkyl)-OR 15 , -C(O)R 12
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle); and
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.
  • the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.
  • Formula (I-a) has the formula: ; wherein all variables are as described for
  • a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X is selected from N and C(R 6 );
  • Z is selected from O, N, C(R 5 ) 2 , C(O), S, S(O), and S(O) 2 ;
  • A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms
  • R 2 , R 5 , R 6 , R 8 , R 9 , and R 10 are each independently selected at each occurrence from hydrogen, halogen, - CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , - SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R 20 ; m is 0, 1, 2, or 3; n is 1 or 2;
  • R 11 is selected from hydrogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)OR 12 , -C(O)OC(O)R 12 , -C(O)O-(C 1-6 alkyl)-OR 15 , -(C 1-6 alkyl)-OR 15 , -C(O)R 12
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and -OH;
  • R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle); and
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I-a) is replaced with a bond to the antigen binding unit or the chemical linker.
  • the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.
  • Formula (I-a) has the formula: ; wherein all variables are as described for
  • a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X is selected from N and C(R 6 );
  • Z is selected from O, N, C(R 5 ) 2 , C(O), S, S(O), and S(O) 2 ;
  • A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms
  • R 2 , R 5 , R 6 , and R 8 are each independently selected at each occurrence from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , - N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R 20 ; m is 0, 1, 2, or 3; n is 1 or 2;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle);
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and -OH;
  • R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle); and
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I-a) is replaced with a bond to the antigen binding unit or the chemical linker.
  • Formula (I-a) has the formula: ; wherein all variables are as described for
  • a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I-b): or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and -OH;
  • R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle); and
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I-b) is replaced with a bond to the antigen binding unit or the chemical linker.
  • the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.
  • the compound of Formula (I-b) is a compound of Formula (I-c): or a pharmaceutically acceptable salt or solvate thereof.
  • (i) X is N; and/or (ii) R 3 is independently selected at each occurrence from C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)- (C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6- membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalky l)-(3- to 12-membered heterocycle)
  • the present disclosure provides a compound of Formula (I-d) applicable for generating a subject conjugate: or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X is selected from C(R 6 ) and N;
  • A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ; R 20 is independently selected at each occurrence from halogen, oxo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 al
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and -OH;
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.
  • the present disclosure provides a compound of Formula (I-e) applicable for generating a subject conjugate,: or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms;
  • R 2 , R 8 , and R 10 are each independently selected at each occurrence from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , - N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )
  • R 9 is selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), - N(R 12 )C(O)OR 12 ,
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 6 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -SF 5 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), - N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R 20 ; m is 0, 1, 2, or 3; n is 1 or 2;
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ;
  • R 10 is halogen.
  • R 10 is -F.
  • R 10 is -Cl.
  • R 10 is -Br.
  • R 10 is C 1-6 alkyl optionally substituted with one, two, or three R 20 .
  • R 10 is C 1-6 alkyl optionally substituted with one, two, or three halogen.
  • compound of Formula (I-e) is selected from
  • X is C(R 6 ), such as C(Cl).
  • X is N.
  • X is C(R 6 ); and R 6 and R 8 are independently selected from hydrogen, halogen, and C 1-3 haloalkyl.
  • X is C(R 6 ); R 6 is selected from chlorine and -CF 3 : and R 8 is fluorine.
  • X is N; and R 8 is selected from hydrogen, halogen, and C 1-3 haloalkyl.
  • X is N; and R 8 is fluorine.
  • X is C(R 6 ); and Z is selected from O and C(R 5 ) 2 . In some embodiments, X is C(R 6 ); and Z is selected from O and CH 2 . In some embodiments, X is C(R 6 ); Z is selected from O and C(R 5 ) 2 : and R 6 and R 8 are independently selected from hydrogen, halogen, and C 1-3 haloalkyl. In some embodiments, X is C(R 6 ); Z is selected from O and C(R 5 ) 2 : R 6 is selected from chlorine and -CF 3 : and R 8 is fluorine.
  • X is C(R 6 ); Z is selected from O and CH 2 : and R 6 and R 8 are independently selected from hydrogen, halogen, and C 1-3 haloalkyl. In some embodiments, X is C(R 6 ); Z is selected from O and CH 2 : R 6 is selected from chlorine and -CF 3 ; and R 8 is fluorine. In some embodiments, X is N; Z is selected from O and CH 2 : and R 8 is selected from hydrogen, halogen, and C 1-3 haloalkyl. In some embodiments, X is N; Z is selected from O and CH 2 : and R 8 is selected from hydrogen, halogen, and C 1-3 haloalkyl. In some embodiments, X is N; Z is selected from O and CH 2 : and R 8 is fluorine. In some embodiments, X is N; Z is selected from O and CH 2 : and R 8 is fluorine. In some embodiments, X is N; Z is selected from O and CH 2 : and
  • R 4 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more R 20 .
  • R 4 is selected from C 1-6 alkyl and -C 0-6 alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more R 20 .
  • R 4 is -C 1-3 alkyl-(3- to 9-membered heterocycle) optionally substituted with one or more R 20 , and further optionally wherein the 3- to 9-membered heterocycle is selected from azetidinyl, thietanyl,
  • R 4 is -C 1-3 alkyl-(pyridine) optionally substituted with one or more R 20 .
  • R 4 is -C 1-3 alkyl-(3- to 9-membered heterocycle), wherein the 3- to 9- membered heterocycle is substituted with -NH 2 .
  • R 4 is -C 1-3 alkyl-(pyridine), wherein the pyridine is substituted with -NH 2 .
  • R 9 is C 1-3 haloalkyl, such as -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , or -CH 2 CF 3 .
  • R 9 is selected from -CH 3 , -CHF 2 , - CH 2 CH 3 , and CH 2 CHF 2 .
  • R 9 is C 1-3 alkyl.
  • R 9 is CH 3 . In some
  • R 9 is selected from -C 1-6 alkyl-(C 3-6 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-6 carbocycle), -C 1-6 alkyl-(3- to 6-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 6-membered heterocycle), wherein -C 1-6 alkyl-(C 3-6 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-6 carbocycle), -C 1-6 alkyl-(3- to 6-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 6-membered heterocycle) are each optionally substituted with one, two, or three substituents selected from oxo, -OR 22 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from oxo, -OR 22 , and -N(
  • R 9 is selected from -C 1-3 alkyl-(C 3-6 carbocycle), -(2- to 3 -membered heteroalky l)-(C 3-6 carbocycle), - C 1-3 alkyl-(4- to 6-membered heterocycle), and -(2- to 3-membered heteroalkyl)-(4- to 6-membered heterocycle), wherein -C 1-3 alkyl-(C 3-6 carbocycle), -(2- to 3-membered heteroalkyl)-(C 3-6 carbocycle), -C 1-3 alkyl-(4- to 6- membered heterocycle), and -(2- to 3 -membered heteroalky l)-(4- to 6-membered heterocycle) are each optionally substituted with one, two, or three substituents selected from oxo, -OCH 3 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from oxo and -NH 2 .
  • R 9 is selected from -C 1-3 alkyl-(C 3-6 saturated carbocycle), -(2- to 3-membered heteroalkyl)-(C 3-6 saturated carbocycle), -C 1-3 alkyl-(4- to 6- membered saturated heterocycle), -(2- to 3-membered hetero alkyl) -(4- to 6-membered saturated heterocycle), -C 1-3 alkyl-(5- to 6-membered heteroaryl), and -(2- to 3-membered heteroalkyl)-(5- to 6-membered heteroaryl), wherein - C 1-3 alkyl-(C 3-6 saturated carbocycle), -(2- to 3-membered heteroalkyl)-(C 3-6 saturated carbocycle), -C 1-3 alkyl-(4- to 6-membered saturated heterocycle), -(2- to 3 -membered hetero alkyl) -(4- to 6-membered saturated heterocycle), -C 1-3 alkyl-(5
  • R 9 is C 1-6 alkyl optionally substituted with one, two, or three substituents selected from halogen, oxo, -OR 22 , -N(R 22 )(R 23 ), -S(O)R 22 , -C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O) 2 R 22 , -P(O)(R 22 )(R 23 ), and
  • R 9 is C 1-6 alkyl optionally substituted with one, two, or three substituents selected from
  • R 10 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, -OR 12 , and -N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 2- to 6-membered heteroalkyl are optionally substituted with one, two, or three R 20 ; or R 9 and R 10 , together with the atoms to which they are attached, form C 4-8 carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 .
  • R 10 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6- membered heteroalkyl, -OR 12 , and -N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 2- to 6-membered heteroalkyl are optionally substituted with one, two, or three R 20 .
  • R 9 and R 10 together with the atoms to which they are attached, form C 4-8 carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 .
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12- membered heterocycle), -C(O)R 12 , and -C(O)N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl- (C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 .
  • R 11 is selected from hydrogen, C 1-6 alkyl, and -C(O)R 12 . In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1-6 alkyl, such as -CH 3 . In some embodiments, R 11 is -C(O)R 12 . In some embodiments, R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle). In some embodiments, R 11 is a bond to the antigen binding unit or the chemical linker.
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R 20 . In some embodiments, R 7 is selected from C 10 aryl and 9-membered heteroaryl, each of which is optionally substituted with one or more R 20 . In some embodiments, R 7 is selected from naphthalenyl and benzothiophenyl, each of which is optionally substituted with one or more R 20 .
  • R 7 is selected from bridged bicyclic C 4-10 cycloalkyl, bridged bicyclic 4- to 10-membered heterocycloalkyl, bridged bicyclic C7-10 aryl, and bridged bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 20 .
  • R 7 is selected from fused bicyclic C 4-10 cycloalkyl, fused bicyclic 4- to 10-membered heterocycloalkyl, fused bicyclic C7-10 aryl, and fused bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 20 .
  • R 7 is selected from C 6-10 aryl and 5- to 10- membered heteroaryl, each of which is optionally substituted with one, two, three, four, or five R 20 .
  • R 7 is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more R 20 .
  • R 7 is naphthyl, optionally substituted with one or more R 20 .
  • R 7 is benzothiophenyl, optionally substituted with one or more R 20 .
  • R 7 is selected from: wherein:
  • Q 1 , Q 3 , and Q 5 are independently selected from N and C(R 1a );
  • X 14 , X 15 , X 17 , and X 18 are independently selected from C(O), C(R 1a ), N, C(R 1a ) 2 , and N(R 1b );
  • X 16 is selected from C, N, and C(R 1a ); each R 1a is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12
  • R 7 is selected from
  • R 7 is substituted with -CF 3 , -CH 3 , and -NH 2 . In some embodiments, R 7 is substituted with -CF 3 and -NH 2 . In some embodiments, R 7 is substituted with -CF 3 , -CH 3 , -F, and -NH 2 . In some embodiments, R 7 is substituted with -CF 3 , - F, and -NH 2 .
  • Z is selected from O and C(R 5 ) 2 ;
  • X is selected from C(R 6 ) and N;
  • R 7 is selected from naphthyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more R 20 ; m is 0 or 1 ; and n is 1 or 2.
  • R 11 is hydrogen; m is 0 or 1 ; and n is 1 or 2.
  • X is C(R 6 );
  • A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;
  • X is N
  • R 11 is hydrogen
  • R 9 is C 1-3 alkyl optionally substituted with one, two, or three R 20 ; m is 0 or 1 ; and n is 1 or 2.
  • A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ;
  • R 11 is hydrogen; and m is 0 or 1.
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ;
  • R 6 and R 8 are independently selected from hydrogen, halogen, and C 1-3 haloalkyl; and m is 0 or 1.
  • R 2 is -OR 12 ;
  • R 3 is independently selected at each occurrence from C 1-6 alkyl optionally substituted with one, two, or three R 20 ; m is 0 or 1 ;
  • R 6 is selected from chlorine and -CF 3 ;
  • R 8 is fluorine
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH 3 ; m is 0 or 1 ;
  • R 6 is selected from chlorine and -CF 3 ;
  • R 8 is fluorine
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH 3 ; m is 0 or 1 ;
  • R 8 is fluorine; and n is 1.
  • X is C(R 6 );
  • Z is O
  • R 6 is selected from chlorine and -CF 3 :
  • R 7 is pyridinyl optionally substituted with one or more R 20 ;
  • R 8 is fluorine; and n is 1.
  • Z is selected from O and C(R 5 ) 2 ;
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH 3 ; m is 0 or 1 ;
  • R 7 is naphthyl optionally substituted with one or more R 20 ;
  • R 8 is fluorine; and n is 1 or 2.
  • the compound of Formula (I) or (I-a) applicable for generating a subject conjugate is selected from:
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 carbocycle, 3- to 10- membered heterocycle, -OR 12 , and -N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 3-10 carbocycle, and 3- to 10- membered heterocycle are optionally substituted with one, two, or three R 20 .
  • R 2 is selected from hydrogen, -(C 0-3 alkylene)-O-(C 0-3 alkylene)-R 20 , C 1-3 alkyl, and 3- to 10-membered heterocycle, wherein each C 0-3 alkylene, C 1-3 alkyl, and 3- to 10-membered heterocycle is optionally substituted with one, two, or three R 20 .
  • R 2 is selected from hydrogen, C 1-3 alkyl, -OR 12 , and 3- to 10-membered heterocycle, wherein C 1-3 alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 .
  • R 2 is OR 12 .
  • R 2 is -O(C 1-3 alkylene)(4- to 10-membered heterocycle), wherein
  • R 2 is -OCH 2 (hexahydro-lH-pyrrolizine) optionally substituted with one, two, or three R 20 .
  • R 2 is substituted with halogen, such as fluorine.
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-6 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-e carbocycle), -C 0-6 alkyl-(3- to 6-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 6-membered heterocycle), -OR 12 , and - N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C3-e carbocycle), -(2- to
  • R 8 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, 2- to 6-membered heteroalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -OR 12 , and -N(R 12 )(R 13 ), wherein C 1-6 alkyl, 2- to 6-membered heteroalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more R 20 .
  • n is 0, 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2.
  • R 2 is selected from hydrogen, C 1-3 alkyl, -OR 12 , and 3- to 10-membered heterocycle, wherein C 1-3 alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 2 is selected from hydrogen, C 1-3 alkyl, -OR 12 , and 3- to 10-membered heterocycle, wherein C 1-3 alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 6 is selected from chlorine and -CTT and
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ; m is 0 or 1 ;
  • R 6 is selected from chlorine and -CF 3 :
  • R 8 is fluorine
  • R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH 3 ; m is 0 or 1 ;
  • R 6 is selected from chlorine and -CF 3 :
  • R 8 is fluorine; and n is 1.
  • a compound of Formula (I), (I-a), (I-b), or (I-c) applicable for generating a subject conjugate has the formula: wherein:
  • Ring A is 6-membered heteroaryl comprising one or two ring nitrogen atoms
  • R 9 is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-3 alkynyl, -C 1-2 alkyl-(C 3-4 saturated carbocycle), and -C 1-2 alkyl-(5- to 6-membered saturated heterocycle); wherein C 1-3 alkyl, C 2-4 alkenyl, C 2-3 alkynyl, -C 1-2 alkyl-(C 3-4 saturated carbocycle), and -C 1-2 alkyl-(5- to 6-membered saturated heterocycle) are each optionally substituted with one or more halogen, R 10 is selected from hydrogen and halogen;
  • R 6 is selected from halogen and -CF 3 ;
  • R 7 is benzothiophenyl optionally substituted with one or more substituents independently selected from -
  • R 8 is halogen; and wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.
  • the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.
  • R 6 is -CF 3 .
  • R 5 is halogen.
  • R 8 is -F.
  • the substituents (for example, R 2 , R 6 , R 7 , R 8 , R 9 , and R 10 ) of formula (I-f) are the same as the corresponding substituents in Formula (I), (I-a), (I-b), and/or (I-c), including in embodiments thereof.
  • a compound of Formula (I-f) is a compound of Formula (I), (I-a), (I-b), and/or (I-c),.
  • a compound of Formula (I), (I-a), (I-b), or (I-c) applicable for generating a subject conjugate has the formula: wherein:
  • R 9 is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-3 alkynyl, -C 1-2 alkyl-(C 3-4 saturated carbocycle), and -C 1-2 alkyl-(5- to 6-membered saturated heterocycle); wherein C 1-3 alkyl, C 2-4 alkenyl, C 2-3 alkynyl, -C 1-2 alkyl-(C 3-4 saturated carbocycle), and -C 1-2 alkyl-(5- to 6-membered saturated heterocycle) are each optionally substituted with one or more -F,
  • R 6 is selected from -Cl and -CF 3 ;
  • R 7 is benzothiophenyl optionally substituted with one or more substituents independently selected from - NH 2 , -CN, and -F;
  • R 8 is -F ; and wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.
  • the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.
  • R 6 is -CF 3 .
  • the substituents (for example, R 2 , R 6 , R 7 , R 8 , R 9 , and R 10 ) of formula (I-f) are the same as the corresponding substituents in Formula (I), (I-a), (I-b), or (I-c), including in embodiments thereof.
  • a compound of Formula (I-d) applicable for generating a subject conjugate is a compound of Formula (I), (I-a), (I-b), or (I-c).
  • a compound of Formula (I), (I-a), (I-b), or (I-c), applicable for generating a subject conjugate has the formula:
  • R 6 is -CF 3 .
  • R 9 is -CH 3 . In some embodiments of the formulae above, R 9 is -CH 2 CH 3 . In some embodiments of the formulae above, R 6 is -Cl. In some embodiments of the formulae above, R 6 is -CF 3 . In some embodiments of the formulae above, R 7 is embodiments of the formulae above, R 7 is In some embodiments of the formulae above, R 7 is
  • a compound of Formula (I), (I-a), (I-b), or (I-c), applicable for generating a subject conjugate has the formula:
  • a compound of Formula (I-g) applicable for generating a subject conjugate is a compound for generating a subject conjugate, of Formula (I), (I-a), (I-b), and/or (I-c).
  • the compound of Formula (I), (I-a), or (I-b), applicable for generating a subject conjugate is selected from: solvate thereof.
  • the compound of Formula (I), (I-a), (I-b), or (I-c), applicable for generating a subject conjugate is selected from: pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I), (I-a), (I- b), or (I-c), applicable for generating a subject conjugate is selected from:
  • the present disclosure provides a compound selected from:
  • the present disclosure provides a compound for generating a subject conjugate selected from:
  • a KRAS inhibitor for generating a subject conjugate described herein such as a compound of Formula (I), (I-a), (I-b), or (I-c) is provided as a substantially pure stereoisomer.
  • the stereoisomer is provided in at least 80% enantiomeric excess, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.
  • atropisomers refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, restricted, or greatly slowed as a result of steric interactions with other parts of the molecule and wherein the substituents at both ends of the single bond are asymmetrical (i.e., optical activity arises without requiring an asymmetric carbon center or stereocenter). Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
  • Atropisomers are enantiomers (or epimers) without a single asymmetric atom.
  • compounds for generating conjugates described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • a compound of Formula 1g may be prepared according to Scheme 1.
  • heteroaryl amine 1c can be formed from chloride la via a nucleophilic aromatic substitution reaction with amine lb. Ring closure to Id can be followed by an oxidation reaction to provide sulfone le, which can be substituted with R 2 upon addition of a suitable alcohol to afford If.
  • Substitution of the aryl bromide with a suitable boronic ester can provide the corresponding R 7 - substituted compound, which may optionally be subjected to one or more subsequent reactions, such as a deprotection, to provide a compound of Formula 1g.
  • a compound of Formula 2e may be prepared according to Scheme 2.
  • heteroaryl ether 2c can be formed from fluoride 2a via a nucleophilic aromatic substitution reaction with alcohol 2b.
  • Ring closure to 2d can be followed by substitution with a suitable boronic ester to provide the corresponding R 7 - substituted compound, which may optionally be subjected to one or more protecting group manipulations to provide a compound of Formula 2e.
  • a conjugate of Formula 3c may be prepared according to Scheme 3.
  • amine 3a may be coupled to linker L to form intermediate 3b.
  • the antigen binding unit can be coupled to the linker to provide a conjugate of Formula 3c.
  • a Kras inhibitor-chemical linker capable of forming a conjugate of the present disclosure comprises i) a Kras inhibitor for producing a conjugate of the present disclosure of Table 1, wherein one hydrogen bonded to a nitrogen of the Kras inhibitor is replaced with a bond to a chemical linker; and ii) a chemical linker of Table 2, wherein in Table 2 indicates an attachment site to the Kras inhibitor.
  • the nitrogen atom of the Kras inhibitor covalently bonded to chemical linker e.g., chemical linker of Table 2 is a nitrogen atom bonded to a benzothiophenyl of the Kras inhibitor.
  • the nitrogen atom of the Kras inhibitor covalently bonded to chemical linker is in an aminomethyl that is bonded to a pyrrolizidine of the Kras inhibitor.
  • the chemical linkers of Table 2 may each covalently be bonded to the nitrogen atom of the aminomethyl bonded to pyrrolizidine of a compound of Table 1 ; for example, the Kras inhibitor-chemical linker conjugate comprises #377 of Table 1, and 1019 of Table 2.
  • the linker-modified Kras compounds comprising compound 148 of Table 1 and one linker selected from the group of chemical linkers 1001— 1018 and 1020-1057, each results in a linker-modified Kras compound with, respectively, an observed mass of 1794.9, 1703.6, 1075.4 [M/2]+H+ (half-mass), 1305.4, 1825.7, 918.2 [M/2]+H+ (half-mass), 1967.8, 1549.4, 1351.7, 1034.2 [M/2]+H+ (half-mass), 1771.8, 1307.4, 1358.2, 1833.6, 834.9 [M/2]+H+ (half-mass), 1036.9 [M/2]+H+ (half-mass), 1748.8, 1872.9 , 1699.9 , 1779.7 , 1642.5, 1870.9 , 1219.5 , 1776.6 , 1118.7 [M/2]+H+ (halfmass), 1596.4, 1745.7, 1878.
  • Each linker-modified Kras compound formed having the observed mass immediately above comprises a bond between the attachment site of the linker and the nitrogen atom of the amine bonded to the benzothiophenyl of compound 148 of Table 1.
  • the linker-modified Kras compound formed by covalently bonding compound 377 of Table 1 and 1019 of Table 2 (between the aminomethyl nitrogen of 377 and the attachment site of 1019) has an observed mass of 1316.7.
  • linker-modified Kras compounds described herein may be further conjugated to any antigen binding unit disclosed herein including but not limited to Cetuximab to yield a subject conjugate.
  • the linker-attached Kras inhibitors described immediately above each comprise a moiety covalently bonded to cetuximab, which can be produced from the of the linkers of Table 2, wherein indicates the attachment site of th
  • Non-limiting examples of conjugates of the present disclosure include:
  • Ab is an antigen binding unit selected from the group of consisting of AG7, B7-H3, BCMA, CA15-3, CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD70, CD71, CD79B, CEA, CLDN18.2, EGFR, FOLR1, GCC, GPC1, HER2, HER3, ICAM1, LeX, LeY, MET, MSLN, MUC1, NECTIN4, SLC44A4, TF, and Trop-2.
  • Ab in the structures shown in this paragraph comprises the amino acid sequence of cetuximab.
  • Ab in the structures shown in this paragraph comprises the amino acid sequence of Sacituzumab.
  • Ab in the structures shown in this paragraph is bonded to the linker through an Ab thiol.
  • m in the structures shown in this paragraph is 2, 4, 6, or 8.
  • m in the structures shown in this paragraph is 4.
  • m in the structures shown in this paragraph is 8.
  • m in the structures shown in this paragraph is 2.
  • Antibody -drug conjugates can also be prepared by methods known in the art and also according to the exemplary procedures provided herein to yield various Kras inhibitor-to-antibody ratio (DAR) ratios, including about 2, 4, 6, 8.
  • DAR Kras inhibitor-to-antibody ratio
  • TCEP tris(2- carboxy ethyljphosphine
  • TCEP tris(2- carboxy ethyljphosphine
  • the reduced antibody is conjugated with excess linker modified Kras inhibitor (5 equiv.) in 10% DMA and the reaction proceeded for 1 h at 22°C.
  • a solution with cysteine (4 equiv.) is added to quench the conjugation reaction by depleting the unconjugated linker-payload.
  • the cell panel include HPAC (KRAS-G12D, pancreatic adenocarcinoma), H1373 (KRAS-G12C, lung adenocarcinoma), H2009 (KRAS-G12A, lung adenocarcinoma), MIA-PaCa2 (KRAS-G12C, pancreatic adenocarcinoma), THP-1 (NRAS-G12D, acute myeloid leukemia), T24 (HRAS-G12V, colorectal adenocarcinoma), and SK -MEL-30 (NRAS-Q61K, melanoma).
  • the present disclosure provides a method of treating a Ras-mediated cancer in a subject in need thereof, comprising administering to the subject a SHP2 inhibitor, a SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4/6 inhibitor, or a BRAF inhibitor and an effective amount of a conjugate described herein.
  • the cancer is a solid tumor.
  • the cancer is a hematological cancer.
  • TI conjugate /Tl KRASi is greater than 1.1, such as greater than 1.2, 1.3, 1.4, 1.5
  • TI conjugate /Tl KRASi is greater than 2. In some embodiments, TI conjugate /Tl KRASi is greater than 5.
  • the present disclosure provides a method of increasing concentration of a small-molecule KRAS inhibitor in tumor tissue, comprising providing a conjugate described herein to a subject, wherein increased tumor tissue concentration is ascertained by the formula: ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t-k /[KRASi] p-k ) > 1, wherein [KRASi] t-c is concentration of the KRAS inhibitor in tumor tissue at a first time -point following administration of the conjugate; wherein [KRASi] p-c is plasma concentration of the KRAS inhibitor at the same time -point following the administration of the conjugate; wherein [KRASi] t-k is concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time -point; and wherein [KRASi] p-k is plasma concentration of the KRAS inhibitor
  • ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t-k /[KRASi] p-k ) is greater than 1.1, such as greater than 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4,
  • ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t-k /[KRASi] p-k ) is greater than 2. In some embodiments, ([KRASi] t-c /[KRASi] p-c ) / ([KRASi] t-k /[KRASi] p-k ) is greater than 5. In some embodiments, the first time-point is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 36 hours, or 48 hours after the administration.
  • efficacy of the conjugate may be greater than efficacy of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration.
  • one or more subject conjugate has been shown to elicit tumor regression more effectively than the antigen binding unit and the Kras inhibitor, when each being administered alone or in combination as separate molecules and not conjugated together to form a cetuximab-Kras ADC-conjugate.
  • cetuximab-Kras conjugates DAR 4 with various linkers elicited tumor regression as early as day 4 after administration, and more than 50% tumor regression on day 22 after administration.
  • toxicity of the conjugate is less than toxicity of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration.
  • Biological properties that can be determined with SPR include but are not limited to adsorption kinetics, desorption kinetics, antigen binding, affinity, epitope mapping, biomolecular structure, protein interaction, biocompatibility, tissue engineering, lipid biolayers, and any combination thereof.
  • the Ras target to which a subject compound binds can be a Ras mutant (e.g., G12S, G12C, G12D, G12V, G13C, and/or G13D), including a mutant of K-Ras, H-Ras, or N-Ras.
  • the methods of treating cancer can be applied to treat a solid tumor or a hematological cancer.
  • the cancer being treated can be, without limitation, prostate cancer, brain cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, various lung cancers including non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, non-Hodgkin’s lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a conjugate described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer.
  • cancer in some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a conjugate described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T- cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma
  • cancer in some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a conjugate described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is one or more cancers selected from the group consisting of chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B- ALL), and/or acute lymphoblastic leukemia (ALL).
  • CLL chronic lymphocytic leukemia
  • AML acute myeloid leukemia
  • T-ALL T-cell acute lymphoblastic leukemia
  • B- ALL B cell acute lymphoblastic leukemia
  • ALL acute lymphoblastic leukemia
  • any of the treatment methods disclosed herein can be administered alone or in combination or in conjunction with another therapy or another agent.
  • “combination” it is meant to include (a) formulating a subject composition containing a subject conjugate together with another agent, or (b) using the subject composition separate from the another agent as an overall treatment regimen.
  • “conjunction” it is meant that the another therapy or agent is administered either simultaneously, concurrently or sequentially with a subject composition comprising a conjugate disclosed herein, with no specific time limits, wherein such conjunctive administration provides a therapeutic effect.
  • chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosf amide, temozolomide), an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoi
  • Anti-cancer agents of particular interest for combinations with a conjugate of the present disclosure include: anthracy clines; alkylating agents; antimetabolites; drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506 or inhibit the p70S6 kinase; mTOR inhibitors; immunomodulators; anthracy clines; vinca alkaloids; proteosome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; a CDK4 kinase inhibitor; a BTK inhibitor; a MKN kinase inhibitor; a DGK kinase inhibitor; or an oncolytic virus.
  • compositions provided herein can be administered in combination with radiotherapy, such as radiation.
  • Whole body radiation may be administered at 12 Gy.
  • a radiation dose may comprise a cumulative dose of 12 Gy to the whole body, including healthy tissues.
  • a radiation dose may comprise from 5 Gy to 20 Gy.
  • a radiation dose may be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12, Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy.
  • Radiation may be whole body radiation or partial body radiation. In the case that radiation is whole body radiation it may be uniform or not uniform. For example, when radiation may not be uniform, narrower regions of a body such as the neck may receive a higher dose than broader regions such as the hips.
  • an immunosuppressive agent can be used in conjunction with a subject treatment method.
  • immunosuppressive agents include but are not limited to cyclosporin, azathioprine, methotrexate, my cophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cy toxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccine, and any combination thereof.
  • the above -described various methods can comprise administering at least one immunomodulatory agent.
  • the at least one immunomodulatory agent is selected from the group consisting of immuno stimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof.
  • the immuno stimulatory agents are selected from the group consisting of IL-12, an agonist costimulatory monoclonal antibody, and combinations thereof.
  • Immunostimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, costimulatory agents, immunogenicity agents, immunomodulators, or immunotherapeutic agents.
  • An immunostimulant can be a cytokine such as an interleukin.
  • One or more cytokines can be introduced with modified cells provided herein. Cytokines can be utilized to boost function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within a tumor microenvironment. In some cases, IL -2 can be used to facilitate expansion of the modified cells described herein. Cytokines such as IL- 15 can also be employed.
  • cytokines in the field of immunotherapy can also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof.
  • An interleukin can be IL -2, or aldesleukin.
  • Aldesleukin can be administered in low dose or high dose.
  • a high dose aldesleukin regimen can involve administering aldesleukin intravenously every 8 hours, as tolerated, for up to about 14 doses at about 0.037 mg/kg (600,000 lU/kg).
  • An immuno stimulant e.g., aldesleukin
  • a conjugate described herein such as a conjugate, salt, or solvate of Formula (A) is administered in combination or in conjunction with one or more pharmacologically active agents selected from (1) an inhibitor of MEK (e.g., MEK1, MEK2) or of mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or of mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, EGF-816); (3) an immunotherapeutic agent (e.g., checkpoint immune blockade agents, as disclosed herein); (4) a taxane (e.g., pac), a paclitotin
  • a conjugate described herein such as a conjugate, salt, or solvate of Formula (A) is administered in combination or in conjunction with one or more additional pharmacologically active agents comprising an inhibitor of SOS (e.g., SOS1, SOS2) or of mutants thereof, such as RMC-5845, or BI-1701963.
  • SOS e.g., SOS1, SOS2
  • RMC-5845 e.g., RMC-5845, or BI-1701963.
  • a conjugate described herein such as a conjugate, salt, or solvate of Formula (A) is administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD- 1 and/or anti-PD-L 1 antibody, anti-CLTA-4 antibody).
  • checkpoint immune blockade agents e.g., anti-PD- 1 and/or anti-PD-L 1 antibody, anti-CLTA-4 antibody.
  • composition comprising at least one conjugate described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients.
  • excipient(s) or carrier(s)
  • the excipient(s) is acceptable or suitable if the excipient is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
  • a conjugate described herein is administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of a conjugate or composition described herein can be affected by any method that enables delivery of the conjugate to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • a conjugate described herein can be administered locally to the area in need of treatment, by, for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
  • the administration can also be by direct injection at the site of a diseased tissue or organ.
  • a conjugate described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.
  • a pharmaceutical composition suitable for oral administration is presented as a discrete unit such as a capsule, cachet or tablet, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary, or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free -flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered conjugate moistened with an inert liquid diluent.
  • the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active conjugate doses.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the conjugates may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the KRAS inhibitor selectively inhibits KRAS or a mutant thereof relative to HRAS and NRAS (e.g., 1.1 fold, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, , 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 5000, or 10000 fold).
  • HRAS and NRAS e.g., 1.1 fold, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, , 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700
  • the antigen binding unit is selected from a monoclonal antibody, a Fab, a Fab’, an F(ab’), an Fv, a disulfide linked Fc, an scFv, a single domain antibody, a diabody, a bi-specific antibody, and a multi-specific antibody.
  • the antigen binding unit is a monoclonal antibody.
  • linker comprises one or more components independently selected from alkyl, polyethylene glycol, a hydrazone, maleimide, succinimide, asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, valine, alanine, glycine, leucine, isoleucine, methionine, tryptophan, proline, histidine, citrulline, phenylalanine, carboxylate, and p-aminobenzyloxycarbonyl.
  • the linker comprises one or more components independently selected from alkyl, polyethylene glycol, a hydrazone, maleimide, succinimide, asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, valine, alanine, glycine, leucine,
  • Z 1 is a product formed by reaction of the antigen binding unit with a reactive precursor of Z 1 ;
  • Z 2 is absent, C 1-6 alkyl, (CH 2 CH 2 O) n2 , -C(O)NH-, -C(O)NCH 3 -, (C(O)CH 2 N(CH 3 )) n2 , -
  • Z 3 is selected from a bond, Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu- Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala-Vai, Val-Val, Val-Gly, Gly-Val, Phe-Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg- Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu
  • R z is selected from hydrogen, -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 CH 3 , -CH 2 N(CH 3 )(C(O)CH 2 N(CH 3 )) n2 -C(O)CH 3 , -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 -CH 2 CH 2 C(O)-(N(CH 3 )CH 2 C(O)) n2 -N(CH 3 ) 2 , -SO 3 H, -CO 2 H, PEG 4-32, polysarcosine, -(CH 2 N(CH 3 )C(O)) n2 CH 3 , and a sugar moiety; nl, n3, and n4 are each independently 0 or 1 ; n2 is independently an integer from 1 to 20; and indicates an attachment site to the KRAS inhibitor.
  • Z 2 is absent, C 1-6 alkyl or -(CH 2 CH 2 O ⁇ CH 2 CH 2 , ;
  • Z 3 is selected from Val-Cit and Val-Ala;
  • R z is selected from hydrogen, -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 CH 3 , -CH 2 N(CH 3 )(C(O)CH 2 N(CH 3 )) n2 -C(O)CH 3 , and -CH 2 N(CH 3 )C(O)-(CH 2 CH 2 O) n2 -CH 2 CH 2 C(O)-(N(CH 3 )CH 2 C(O)) n2 -N(CH 3 ) 2 ; n1, n3, and n4 are each independently 0 or 1 ; n2 is independently an integer from 1 to 20; and indicates an attachment site to the KRAS inhibitor.
  • Z is selected from O, N, C(R 5 ) 2 , C(O), S, S(O), and S(O) 2 ;
  • R 3 is independently selected at each occurrence from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O
  • R 4 is selected from hydrogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalky l)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR 12 , -C(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O) 2 R 12 , - S(O)(NR 12 )R 12 , -S(O) 2 N(R
  • R 7 is selected from C 6-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R 20 ; m is 0, 1, 2, or 3; n is 1 or 2;
  • R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, - C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl- (C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and -OH;
  • R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle); and
  • R 23 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.
  • a pharmaceutical composition comprising the conjugate of any one of embodiments 1 to 127, or a salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a conjugate of any one of embodiments 1 to 127, or a salt thereof. 130.
  • a method of treating cancer in a subject comprising a Ras mutant protein comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a conjugate of any one of embodiments 1 to 127, or a salt thereof.
  • 131. The method of embodiment 129-130, wherein the cancer is a solid tumor or a hematological cancer.
  • 132. The method of any one of embodiments 129-131, wherein the cancer comprises a K-Ras G12C, G12D, G12S, or G12V mutant protein.
  • a method of modulating signaling output of a Ras protein comprising contacting a Ras protein with an effective amount of a conjugate of any one of embodiments 1 to 127, or a salt thereof, thereby modulating the signaling output of the Ras protein.
  • a method of inhibiting cell growth comprising administering an effective amount of a conjugate of any one of embodiments 1 to 127, or a salt thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells. 135.
  • the method of any one of embodiments 129-134 comprising administering an additional agent.
  • a method of delivering a small-molecule KRAS inhibitor that exhibits low permeability as characterized by a PAMPA assay comprising contacting a tumor cell with a conjugate of any one of embodiments 1 to 127, or a salt thereof, wherein the KRAS inhibitor exhibits a PAMPA permeability (P e ) value less than 1 x 10 -6 cm/s.
  • a method of enhancing therapeutic efficacy of a small-molecule KRAS inhibitor comprising providing a conjugate of any one of embodiments 1 to 127 to a subject, wherein enhanced therapeutic efficacy is ascertained by the formula:
  • a method of reducing plasma concentration of a small-molecule KRAS inhibitor comprising providing a conjugate of any one of embodiments 1 to 127 to a subject, wherein reduced plasma concentration is ascertained by the formula:
  • a method of increasing concentration of a small-molecule KRAS inhibitor in tumor tissue comprising providing a conjugate of any one of embodiments 1 to 127 to a subject, wherein increased tumor tissue concentration is ascertained by the formula:
  • a method of delivering a small -molecule KRAS inhibitor to the central nervous system of a subject comprising administering a conjugate of any one of embodiments 1 to 127 to the subject, wherein the KRAS inhibitor is released from the conjugate after entering the CNS of the subject.
  • a method of generating a slow-release form of a small-molecule KRAS inhibitor the method comprising conjugating an antigen binding unit to a small-molecule KRAS inhibitor through a chemical linker, wherein the small-molecule inhibitor is released from the conjugate upon introducing the conjugate into a subject or a cell.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés et des sels pharmaceutiquement acceptables de ceux-ci, et des procédés d'utilisation de ceux-ci. Les composés et les procédés ont une gamme d'utilités en tant qu'agents thérapeutiques, diagnostics et outils de recherche. En particulier, les compositions et les procédés de l'invention sont utiles pour réduire la sortie de signalisation d'une protéine oncogène.
PCT/US2025/014660 2024-02-06 2025-02-05 Conjugués hétérocycliques et leurs utilisations Pending WO2025171055A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202463550553P 2024-02-06 2024-02-06
US63/550,553 2024-02-06
US202463700538P 2024-09-27 2024-09-27
US63/700,538 2024-09-27

Publications (1)

Publication Number Publication Date
WO2025171055A1 true WO2025171055A1 (fr) 2025-08-14

Family

ID=94869581

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/014660 Pending WO2025171055A1 (fr) 2024-02-06 2025-02-05 Conjugués hétérocycliques et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2025171055A1 (fr)

Citations (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR901228A (fr) 1943-01-16 1945-07-20 Deutsche Edelstahlwerke Ag Système d'aimant à entrefer annulaire
WO2010093395A1 (fr) 2009-02-13 2010-08-19 Immunomedics, Inc. Immunoconjugués avec une liaison intracellulaire clivable
WO2013173337A2 (fr) 2012-05-15 2013-11-21 Seattle Genetics, Inc. Conjugués de lieurs à auto-stabilisation
WO2014160200A1 (fr) 2013-03-13 2014-10-02 Dana-Farber Cancer Institute, Inc. Inhibiteurs de ras et leurs utilisations
WO2015095755A1 (fr) 2013-12-19 2015-06-25 Seattle Genetics, Inc. Liants à base de carbamate de méthylène à utiliser avec des conjugués de médicaments ciblés
US20150239900A1 (en) 2013-10-10 2015-08-27 Araxes Pharma Llc Inhibitors of kras g12c
WO2016176338A1 (fr) 2015-04-30 2016-11-03 The Trustees Of Columbia University In The City Of New York Ligands ras de petites molécules
WO2016179558A1 (fr) 2015-05-06 2016-11-10 The Regents Of The University Of California Modulateurs de k-ras
WO2017087528A1 (fr) 2015-11-16 2017-05-26 Araxes Pharma Llc Composés quinazoline substitués en position 2 comprenant un groupe hétérocyclique substitué et leur méthode d'utilisation
US9862701B2 (en) 2014-09-25 2018-01-09 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US20180086753A1 (en) 2015-04-15 2018-03-29 Araxes Pharma Llc Fused-tricyclic inhibitors of kras and methods of use thereof
US20180127396A1 (en) 2016-10-07 2018-05-10 Araxes Pharma Llc Inhibitors of ras and methods of use thereof
WO2018112240A1 (fr) 2016-12-14 2018-06-21 Progenity Inc. Traitement d'une maladie du tractus gastro-intestinal avec un inhibiteur du tnf
WO2018115380A1 (fr) 2016-12-22 2018-06-28 Boehringer Ingelheim International Gmbh Nouvelles quinazolines à substitution benzylamino et leurs dérivés en tant qu'inhibiteurs de sos1
WO2018143315A1 (fr) 2017-02-02 2018-08-09 アステラス製薬株式会社 Composé de quinazoline
US20180273515A1 (en) 2015-09-28 2018-09-27 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2018172250A1 (fr) 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
US20180273523A1 (en) 2015-09-28 2018-09-27 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20180282307A1 (en) 2015-09-28 2018-10-04 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20180282308A1 (en) 2015-09-28 2018-10-04 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2018195349A1 (fr) 2017-04-19 2018-10-25 California Institute Of Technology Catalyse de réaction de dégagement d'oxygène
US20180319775A1 (en) 2015-09-28 2018-11-08 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2018206539A1 (fr) 2017-05-11 2018-11-15 Astrazeneca Ab Composés hétéroaryle inhibant des protéines ras portant la mutation g12c
US20180334454A1 (en) 2017-05-22 2018-11-22 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2018218070A2 (fr) 2017-05-25 2018-11-29 Araxes Pharma Llc Inhibiteurs covalents de kras
WO2018218069A1 (fr) 2017-05-25 2018-11-29 Araxes Pharma Llc Dérivés de quinazoline utilisés en tant que modulateurs de kras, hras ou nras mutants
WO2018218071A1 (fr) 2017-05-25 2018-11-29 Araxes Pharma Llc Composés et leurs procédés d'utilisation pour le traitement du cancer
US10144724B2 (en) 2015-07-22 2018-12-04 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US20190055211A1 (en) 2015-09-28 2019-02-21 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2019051291A1 (fr) 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US20190092767A1 (en) 2015-09-28 2019-03-28 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US10246424B2 (en) 2015-04-10 2019-04-02 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
WO2019081455A1 (fr) 2017-10-23 2019-05-02 Mablink Bioscience Conjugué ligand-médicament comprenant une polysarcosine de masse moléculaire unique
US10280172B2 (en) 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US20190144444A1 (en) 2017-11-15 2019-05-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2019107519A1 (fr) 2017-11-29 2019-06-06 株式会社ブリヂストン Composition de caoutchouc destinée à une semelle de pied prothétique et semelle de pied prothétique
WO2019104505A1 (fr) 2017-11-29 2019-06-06 中车资阳机车有限公司 Système de charge destiné à une batterie d'alimentation montée sur véhicule d'une locomotive à alimentation hybride diesel-électrique
WO2019122129A1 (fr) 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
WO2019141250A1 (fr) 2018-01-19 2019-07-25 南京明德新药研发股份有限公司 Dérivé de pyridone-pyrimidine agissant en tant qu'inhibiteur de mutéine krasg12c
WO2019150305A1 (fr) 2018-02-01 2019-08-08 Pfizer Inc. Dérivés de quinazoline et de pyridopyrimidine substitués utiles en tant qu'agents anticancéreux
WO2019155399A1 (fr) 2018-02-09 2019-08-15 Pfizer Inc. Dérivés de tétrahydroquinazoline utiles en tant qu'agents anticancéreux
WO2019204442A1 (fr) 2018-04-18 2019-10-24 Theras, Inc. Modulateurs de k-ras possédant une fraction cyanoacrylamide
WO2019204449A1 (fr) 2018-04-18 2019-10-24 Theras, Inc. Modulateurs de k-ras comprenant une fraction vinylsulfone
WO2019201848A1 (fr) 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
WO2019213516A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019213526A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019217691A1 (fr) 2018-05-10 2019-11-14 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2019217307A1 (fr) 2018-05-07 2019-11-14 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2019215203A1 (fr) 2018-05-08 2019-11-14 Astrazeneca Ab Composés hétéroaryles tétracycliques
WO2019241157A1 (fr) 2018-06-11 2019-12-19 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2020027083A1 (fr) 2018-07-31 2020-02-06 アステラス製薬株式会社 Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif
WO2020027084A1 (fr) 2018-07-31 2020-02-06 アステラス製薬株式会社 Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif
WO2020035031A1 (fr) 2018-08-16 2020-02-20 Genentech, Inc. Composés cycliques condensés
WO2020047192A1 (fr) 2018-08-31 2020-03-05 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2020180770A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétérocyclyle bicycliques et leurs utilisations
WO2020180768A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
WO2020236841A2 (fr) 2019-05-20 2020-11-26 Novartis Ag Conjugués anticorps-médicament ayant des lieurs comprenant des groupes hydrophiles
WO2021092115A1 (fr) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations
WO2021127429A1 (fr) 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022047260A1 (fr) 2020-08-28 2022-03-03 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2022228494A1 (fr) 2021-04-29 2022-11-03 上海汇连生物医药有限公司 Procédé de préparation et application d'un médicament conjugué à un anticorps
WO2022271658A1 (fr) * 2021-06-23 2022-12-29 Erasca, Inc. Inhibiteurs de kras tricycliques
WO2023102875A1 (fr) 2021-12-10 2023-06-15 Multitude Therapeutics Inc. Conjugué anticorps-médicament anti-cdh6
WO2023250391A2 (fr) * 2022-06-22 2023-12-28 New York University Compositions et méthodes comprenant des anticorps qui se lient à des conjugués peptidiques covalents
WO2024015262A1 (fr) * 2022-07-09 2024-01-18 Blossomhill Therapeutics, Inc. Inhibiteurs de kras à cycles fusionnés pour le traitement d'une maladie
WO2024085661A1 (fr) * 2022-10-18 2024-04-25 Ildong Pharmaceutical Co., Ltd. Nouveaux composés tri-hétérocycliques
WO2025007000A1 (fr) * 2023-06-30 2025-01-02 Kumquat Biosciences Inc. Composés aminés tricycliques condensés substitués et leurs utilisations en tant qu'inhibiteurs de ras

Patent Citations (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR901228A (fr) 1943-01-16 1945-07-20 Deutsche Edelstahlwerke Ag Système d'aimant à entrefer annulaire
WO2010093395A1 (fr) 2009-02-13 2010-08-19 Immunomedics, Inc. Immunoconjugués avec une liaison intracellulaire clivable
WO2013173337A2 (fr) 2012-05-15 2013-11-21 Seattle Genetics, Inc. Conjugués de lieurs à auto-stabilisation
WO2014160200A1 (fr) 2013-03-13 2014-10-02 Dana-Farber Cancer Institute, Inc. Inhibiteurs de ras et leurs utilisations
US20150239900A1 (en) 2013-10-10 2015-08-27 Araxes Pharma Llc Inhibitors of kras g12c
WO2015095755A1 (fr) 2013-12-19 2015-06-25 Seattle Genetics, Inc. Liants à base de carbamate de méthylène à utiliser avec des conjugués de médicaments ciblés
US9862701B2 (en) 2014-09-25 2018-01-09 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10246424B2 (en) 2015-04-10 2019-04-02 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US20180086753A1 (en) 2015-04-15 2018-03-29 Araxes Pharma Llc Fused-tricyclic inhibitors of kras and methods of use thereof
WO2016176338A1 (fr) 2015-04-30 2016-11-03 The Trustees Of Columbia University In The City Of New York Ligands ras de petites molécules
WO2016179558A1 (fr) 2015-05-06 2016-11-10 The Regents Of The University Of California Modulateurs de k-ras
US10144724B2 (en) 2015-07-22 2018-12-04 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US20190092767A1 (en) 2015-09-28 2019-03-28 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20190055211A1 (en) 2015-09-28 2019-02-21 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20180282307A1 (en) 2015-09-28 2018-10-04 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20180319775A1 (en) 2015-09-28 2018-11-08 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20180273515A1 (en) 2015-09-28 2018-09-27 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20180282308A1 (en) 2015-09-28 2018-10-04 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US20180273523A1 (en) 2015-09-28 2018-09-27 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2017087528A1 (fr) 2015-11-16 2017-05-26 Araxes Pharma Llc Composés quinazoline substitués en position 2 comprenant un groupe hétérocyclique substitué et leur méthode d'utilisation
US20170197945A1 (en) 2015-11-16 2017-07-13 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US10280172B2 (en) 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US20180127396A1 (en) 2016-10-07 2018-05-10 Araxes Pharma Llc Inhibitors of ras and methods of use thereof
WO2018112240A1 (fr) 2016-12-14 2018-06-21 Progenity Inc. Traitement d'une maladie du tractus gastro-intestinal avec un inhibiteur du tnf
WO2018115380A1 (fr) 2016-12-22 2018-06-28 Boehringer Ingelheim International Gmbh Nouvelles quinazolines à substitution benzylamino et leurs dérivés en tant qu'inhibiteurs de sos1
WO2018143315A1 (fr) 2017-02-02 2018-08-09 アステラス製薬株式会社 Composé de quinazoline
WO2018172250A1 (fr) 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
WO2018195349A1 (fr) 2017-04-19 2018-10-25 California Institute Of Technology Catalyse de réaction de dégagement d'oxygène
WO2018206539A1 (fr) 2017-05-11 2018-11-15 Astrazeneca Ab Composés hétéroaryle inhibant des protéines ras portant la mutation g12c
US20180334454A1 (en) 2017-05-22 2018-11-22 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2018218071A1 (fr) 2017-05-25 2018-11-29 Araxes Pharma Llc Composés et leurs procédés d'utilisation pour le traitement du cancer
WO2018218069A1 (fr) 2017-05-25 2018-11-29 Araxes Pharma Llc Dérivés de quinazoline utilisés en tant que modulateurs de kras, hras ou nras mutants
WO2018218070A2 (fr) 2017-05-25 2018-11-29 Araxes Pharma Llc Inhibiteurs covalents de kras
WO2019051291A1 (fr) 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019081455A1 (fr) 2017-10-23 2019-05-02 Mablink Bioscience Conjugué ligand-médicament comprenant une polysarcosine de masse moléculaire unique
US20190144444A1 (en) 2017-11-15 2019-05-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2019107519A1 (fr) 2017-11-29 2019-06-06 株式会社ブリヂストン Composition de caoutchouc destinée à une semelle de pied prothétique et semelle de pied prothétique
WO2019104505A1 (fr) 2017-11-29 2019-06-06 中车资阳机车有限公司 Système de charge destiné à une batterie d'alimentation montée sur véhicule d'une locomotive à alimentation hybride diesel-électrique
WO2019122129A1 (fr) 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
WO2019141250A1 (fr) 2018-01-19 2019-07-25 南京明德新药研发股份有限公司 Dérivé de pyridone-pyrimidine agissant en tant qu'inhibiteur de mutéine krasg12c
WO2019150305A1 (fr) 2018-02-01 2019-08-08 Pfizer Inc. Dérivés de quinazoline et de pyridopyrimidine substitués utiles en tant qu'agents anticancéreux
WO2019155399A1 (fr) 2018-02-09 2019-08-15 Pfizer Inc. Dérivés de tétrahydroquinazoline utiles en tant qu'agents anticancéreux
WO2019204449A1 (fr) 2018-04-18 2019-10-24 Theras, Inc. Modulateurs de k-ras comprenant une fraction vinylsulfone
WO2019204442A1 (fr) 2018-04-18 2019-10-24 Theras, Inc. Modulateurs de k-ras possédant une fraction cyanoacrylamide
WO2019201848A1 (fr) 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
WO2019213516A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019213526A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019217307A1 (fr) 2018-05-07 2019-11-14 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2019215203A1 (fr) 2018-05-08 2019-11-14 Astrazeneca Ab Composés hétéroaryles tétracycliques
WO2019217691A1 (fr) 2018-05-10 2019-11-14 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2019241157A1 (fr) 2018-06-11 2019-12-19 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2020027083A1 (fr) 2018-07-31 2020-02-06 アステラス製薬株式会社 Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif
WO2020027084A1 (fr) 2018-07-31 2020-02-06 アステラス製薬株式会社 Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif
WO2020035031A1 (fr) 2018-08-16 2020-02-20 Genentech, Inc. Composés cycliques condensés
WO2020047192A1 (fr) 2018-08-31 2020-03-05 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2020180770A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétérocyclyle bicycliques et leurs utilisations
WO2020180768A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
WO2020236841A2 (fr) 2019-05-20 2020-11-26 Novartis Ag Conjugués anticorps-médicament ayant des lieurs comprenant des groupes hydrophiles
WO2021092115A1 (fr) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations
WO2021127429A1 (fr) 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022047260A1 (fr) 2020-08-28 2022-03-03 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2022228494A1 (fr) 2021-04-29 2022-11-03 上海汇连生物医药有限公司 Procédé de préparation et application d'un médicament conjugué à un anticorps
WO2022271658A1 (fr) * 2021-06-23 2022-12-29 Erasca, Inc. Inhibiteurs de kras tricycliques
WO2023102875A1 (fr) 2021-12-10 2023-06-15 Multitude Therapeutics Inc. Conjugué anticorps-médicament anti-cdh6
WO2023250391A2 (fr) * 2022-06-22 2023-12-28 New York University Compositions et méthodes comprenant des anticorps qui se lient à des conjugués peptidiques covalents
WO2024015262A1 (fr) * 2022-07-09 2024-01-18 Blossomhill Therapeutics, Inc. Inhibiteurs de kras à cycles fusionnés pour le traitement d'une maladie
WO2024085661A1 (fr) * 2022-10-18 2024-04-25 Ildong Pharmaceutical Co., Ltd. Nouveaux composés tri-hétérocycliques
WO2025007000A1 (fr) * 2023-06-30 2025-01-02 Kumquat Biosciences Inc. Composés aminés tricycliques condensés substitués et leurs utilisations en tant qu'inhibiteurs de ras

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BERGE S.M. ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1997, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
KATAOKA MASAHIRO ET AL: "Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRAS G12D Inhibitor, in Colorectal Cancer Treatment", ANTICANCER RESEARCH, vol. 43, no. 10, 29 September 2023 (2023-09-29), pages 4341 - 4348, XP093218285, ISSN: 0250-7005, DOI: 10.21873/anticanres.16629 *
O'SULLIVAN �ABHA ET AL: "Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer", vol. 15, no. 6, 7 March 2023 (2023-03-07), CH, pages 1635, XP093275563, ISSN: 2072-6694, Retrieved from the Internet <URL:https://www.mdpi.com/2072-6694/15/6/1635/pdf> DOI: 10.3390/cancers15061635 *
REMINGTONGENNARO: "The Science and Practice of Pharmacy", 2005, MACK PUB. CO.

Similar Documents

Publication Publication Date Title
JP7259104B2 (ja) 抗ｔｒｏｐ２抗体－薬物コンジュゲート
CN110300601B (zh) 吡咯并苯并二氮杂䓬-抗体缀合物
CN107001479B (zh) 抗her2抗体和免疫缀合物
AU2024205004A1 (en) Anti-EGFR antibody drug conjugates
WO2019084060A1 (fr) Conjugués et leurs procédés d&#39;utilisation pour l&#39;administration sélective d&#39;agents immunomodulateurs
CA3099920A1 (fr) Conjugues anticorps-medicament modulateurs d&#39;epissage et procedes d&#39;utilisation
EP3634401A1 (fr) Conjugués de construction d&#39;anticorps
TW202144010A (zh) Ｎｅｃｔｉｎ－４抗體共軛物及其用途
RS61452B1 (sr) Anti-cd123 antitela i njihovi konjugati i derivati
EP3576782A1 (fr) Compositions de produit de recombinaison-peptide et leurs méthodes d&#39;utilisation
HK1207972A1 (en) Immunoconjugates comprising anti - cd79b antibodies
EP2848686B1 (fr) Conjugué d&#39;anticorps anti-cdh3 (p-cadhérine) et médicament
WO2021195598A2 (fr) Conjugués d&#39;anticorps-agent de dégradation et leurs procédés d&#39;utilisation
TW202313122A (zh) 與ｒｏｒ１和ｂ７－ｈ３結合抗體－藥物偶聯物及其用途
CA3114931A1 (fr) Conjugues anticorps-medicament modulateur d&#39;epissage d&#39;herboxidiene et procedes de utilisation
CA3151322A1 (fr) Polytherapie comprenant des conjugues immunostimulants
CN120641419A (zh) 杂环及其用途
CN117396232A (zh) 使用抗cd79b免疫缀合物治疗弥漫性大b细胞淋巴瘤的方法
CN115916822A (zh) 使用抗CD79b免疫缀合物的方法
WO2025171055A1 (fr) Conjugués hétérocycliques et leurs utilisations
WO2025059366A1 (fr) Inhibiteurs de ras
WO2024211235A1 (fr) Conjugués anticorps-médicament et leurs utilisations
TW202404646A (zh) 抗cdh6抗體-藥物結合物之給藥方案
JP2024545138A (ja) 親和性が改善された抗体薬物複合体、その調製法、及びその応用
WO2024211234A1 (fr) Conjugués anticorps-médicament et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25710586

Country of ref document: EP

Kind code of ref document: A1