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WO2019204442A1 - Modulateurs de k-ras possédant une fraction cyanoacrylamide - Google Patents

Modulateurs de k-ras possédant une fraction cyanoacrylamide Download PDF

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Publication number
WO2019204442A1
WO2019204442A1 PCT/US2019/027876 US2019027876W WO2019204442A1 WO 2019204442 A1 WO2019204442 A1 WO 2019204442A1 US 2019027876 W US2019027876 W US 2019027876W WO 2019204442 A1 WO2019204442 A1 WO 2019204442A1
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iii
alkyl
cycloalkyl
heterocycloalkyl
formula
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PCT/US2019/027876
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Inventor
Anna E. Maciag
David Turner
Matthew Alexander James Duncton
Adam R. Renslo
Eddy Low
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University of California Berkeley
University of California San Diego UCSD
Leidos Biomedical Research Inc
Theras Inc
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University of California Berkeley
University of California San Diego UCSD
Leidos Biomedical Research Inc
Theras Inc
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Publication of WO2019204442A1 publication Critical patent/WO2019204442A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure relates generally to compounds that inhibit K-Ras, or the post-translational processing of KRAS that produces a K-Ras protein, and more specifically to inhibitors with a cyanoacryl amide moiety.
  • KRAS is one of the most frequently mutated oncogenes implicated in human cancer.
  • the KiM-S' oncogene encodes the K-Ras protein, which is part of the RAS/MAPK signaling pathway.
  • K-Ras is a GTPase that acts as a molecular switch, flipping between an active GTP-bound form and an inactive GDP -bound form.
  • the K-Ras protein plays a crucial role in tissue signaling, and is involved in cell proliferation, cell differentiation, and apoptosis. Activating mutations in KRAS are common in many different human cancers.
  • effective inhibitors of K-Ras and effective inhibitors of the post- translational processing of KRAS that produces a mature, full-processed K-Ras protein.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
  • A is piperidinyl and B is phenyl or thiophenyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
  • X is -S(O)-, -S(0)2-, -S(0)NR c50 -, -C(S)-, -C(O)-, or -C(R c7 ) 2- ;
  • each R c7 is independently hydrogen, halo, alkyl, or haloalkyl
  • R cl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NR c8 R c9 , -OR cl °, and -SC R c11 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R c4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCh, -CN, -SO2NH2, - NR C 8R C9 , _0R c I °, 0, -SR c51 , and -S0 2 R c11 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R c2 and R c3 together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • each R c5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R c23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R c62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R c54 , R c55 , R c56 , R c57 , R c58 , R c59 , R c60 , and R c61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R cl2 , R cl ⁇ R cl4 , R cl7 , R cl8 , R cl9 , R c20 , R c21 , R c22 , and R c23 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R c62 is independently unsubstituted or substituted with one or more substituents independently selected
  • each R c24 , R c25 , R c26 , R c40 , R c41 , R c42 , R c43 , and R c44 is independently hydrogen, alkyl, or haloalkyl;
  • v is an integer from 0 to 11.
  • Z is aryl or heteroaryl.
  • A is 5- or 6-membered heterocycloalkyl.
  • the compound of Formula (III) is a compound of Formula (III-
  • the compound of Formula (III) is a compound of Formula (III- A-ii):
  • the compound of Formula (III) is a compound of Formula (III- B):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2- -S(0)r-, -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ; r is 0, 1, or 2; and
  • B, Z, X, R c4 , R c5 , R c6 , n, and v are as defined for Formula (III).
  • the compound of Formula (III) is a compound of Formula (III- B-ii):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2-, -S(0)r-, -O-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r is 0, 1, or 2;
  • d is an integer from 0 to 5; and
  • B, X, R c4 , R c5 , R c6 , and n are as defined for Formula (IP).
  • Y is -CH2-.
  • B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three heteroatoms independently selected from the group consisting of O, N, and S.
  • B is a 9- or 10-membered bicyclic heteroaryl comprising one to three heteroatoms independently selected from the group consisting of O, N, and S.
  • B is a (C9- Cio)bicyclic aryl.
  • B is a (C5-Cio)cycloalkyl.
  • Z is a 5-membered heteroaryl.
  • Z is a 9- membered heteroaryl.
  • Z is a 6-membered heteroaryl.
  • Z is alkyl or cycloalkyl.
  • the compound of Formula (III) is a compound of Formula (III- A-i):
  • the compound of Formula (III) is a compound of Formula (III- B-i):
  • the compound of Formula (III) is a compound of Formula (III-A-iii):
  • the compound of Formula (III) is a compound of Formula (III- B-iii):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2-, -S(0)— , -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r is 0, 1, or 2;
  • d is an integer from 0 to 5; and
  • X, R c4 , R c5 , and R c6 are as defined for Formula (III).
  • At least one R c5 is: wherein:
  • R c30 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R c31 and R c32 is independently hydrogen, halo, or alkyl
  • each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR c37 , and
  • each R c33 , R c34 , R c35 , R c36 , R c37 , R c38 , R c39 , R c45 , R c46 , R c47 , and R c48 is independently hydrogen, alkyl, or haloalkyl;
  • X is -S(0)2- In other variations, X is -C(O)-. In still further variations, X is -CH2- In some variations, n is 1 or 2. In certain variations, m is 0. In some variations, p is 0.
  • a pharmaceutical composition comprising a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
  • the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer
  • a method of treating a disorder in a subject in need thereof by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the compound of Formula (III) is a compound of Formula (III- A), Formula (III-A- i), Formula (III-A-ii), Formula (III-A-iii), Formula (PI-B), Formula (III-B-i), Formula (III-B- ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B- iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
  • the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B- iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof for use in a method of treating a disorder in a subject in need thereof.
  • the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
  • the disorder is cancer.
  • the cancer is a blood cancer, or a solid tumor.
  • the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • the disorder is associated with a mutation of K-Ras.
  • a compound such as a compound of Formula (III), Formula (III- A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III- B-i), Formula (III-B-ii), or Formula (PI-B-iii), or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing, as described below.
  • this compound or stereoisomer or pharmaceutically acceptable salt thereof may inhibit K-Ras, or may inhibit the post-translational processing of KRAS that produces a K-Ras protein, such as K-Ras4b.
  • this compound may block the farnesylation of the newly synthesized K-Ras, preventing its C-terminal processing.
  • this compound or stereoisomer or pharmaceutically acceptable salt thereof may be administered to a subject in need thereof, for example in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.
  • a compound or stereoisomer or pharmaceutically acceptable salt thereof as described herein may be administered in a therapeutically effective amount to a subject in need thereof in a method of treating a disorder in a subject.
  • the disorder may be, for example, a disorder associated with a mutation of KRAS.
  • the disorder may be, for example, a disorder associated with a mutation in a K-Ras protein.
  • the compound or stereoisomer or pharmaceutically acceptable salt thereof inhibits K-Ras, or decreases the level of K-Ras, or inhibits the post-translational processing of KRAS to produce a mature, fully-processed K-Ras protein, such as K-Ras4b.
  • the compounds, stereoisomers, and pharmaceutically acceptable salts thereof; compositions comprising said compounds, stereoisomers, and pharmaceutically acceptable salts thereof; and methods of using said compounds stereoisomers, and pharmaceutically acceptable salts thereof and compositions of the present disclosure are described in greater detail below I.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
  • A is piperidinyl and B is phenyl or thiophenyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
  • X is -S(O)-, -S(0) 2- - S(0)NR c50 -, -C(S)-, -C(O)-, or -C(R c7 ) 2- ;
  • each R c7 is independently hydrogen, halo, alkyl, or haloalkyl
  • R cl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR c8 R c9 , -OR cl °, and -S02R c11 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R c4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR C8 R c9 , -OR c1 °, 0, -SR c51 , and -S0 2 R c11 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -NIL ⁇ , -NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SO3H, -SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHSO2H, -NHC(0)
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four R c4 , together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R c2 and R c3 together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • each R c5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R c23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo,
  • each R c62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R c54 , R c55 , R c56 , R c57 , R c58 , R c59 , R cS0 , and R c61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
  • heterocycloalkyl aryl, heteroaryl, alkynyl, or haloalkynyl
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR C24 R c25 , -OR c26 , and -SFs;
  • each R c6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -SO2NH2, -CN, -SF5, -NO2,
  • each R c27 , R c28 , and R c29 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • v is an integer from 0 to 11.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl
  • A is piperidinyl and B is phenyl or thiophenyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
  • X is -S(O)-, -S(0)2-, -S(0)NR c50 -, -C(S)-, -C(O)-, or -C(R c7 ) 2- ;
  • each R c7 is independently hydrogen, halo, alkyl, or haloalkyl
  • R cl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NR c8 R c9 , -OR cl °, and -S02R c11 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each R c4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCh, -CN, -SO2NH2, -NR C8 R c9 , -OR c1 °, 0, -SR c51 , and -SCkR c11 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl
  • R c4 together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R c3 and one R c4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R c2 and R c3 together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • each R c5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NC , -CN,
  • each R c23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R c62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R cl2 , R cl3 , R cl4 , R cl5 , R cl6 , R cl7 , R cl8 , R cl9 , R c20 , R c21 , R c22 , R c52 , R c53 , R c54 , R c55 , R c56 , R c57 , R c58 , R c59 , R c60 , and R c61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R cl2 , R cl3 , R cl4 , R cl7 ,
  • each R c24 , R c25 , R c26 , R c40 , R c41 , R c42 , R c43 , and R c44 is independently hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 11
  • v is an integer from 0 to 11.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Z is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl
  • A is piperidinyl and B is phenyl or thiophenyl
  • Z is hydrogen, alkyl, cycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
  • X is -S(O)-, -S(0)2-, -S(0)NR c50 -, -C(S)-, -C(O)-, or -C(R c7 ) 2- ;
  • each R c7 is independently hydrogen, halo, alkyl, or haloalkyl
  • R cl is hydrogen, alkyl, or cycloalkyl
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, SO2NH2, -NR c8 R c9 , -OR cl °, and -S0 2 R cU , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R c4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR C8 R c9 , -OR c1 °, 0, -SR c51 , and -SC>2R c11 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is independently unsubstituted or substituted with one or more halo; each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
  • R c2 and R c3 together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl;
  • each R c5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R c62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 63.ch R cl5 R cl6 R cl7 J ⁇ cl8 cl9 j ⁇ c52 j ⁇ c53 j ⁇ c54 j ⁇ c55 j ⁇ c56 j ⁇ c57 J ⁇ c58 j ⁇ c59
  • R c60 , and R c61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
  • each R cl2 , R cl3 , R c20 , R c21 , and R c22 is independently hydrogen, alkyl
  • each R cl4 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
  • each R c24 , R c25 , R c26 , R c40 , R c41 , R c42 , R c43 , and R c44 is independently hydrogen, alkyl, or haloalkyl;
  • each R c6 is independently selected from the group consisting of halo, alkyl, haloalkyl,
  • each R c27 , R c28 , and R c29 is independently hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • A is a 4-, 5-, 6-, or 7-membered heterocycloalkyl.
  • A is a 5-, 6-, or 7-membered heterocycloalkyl. In some embodiments, A is a 5-, 6-, or 7-membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, A is a 5- or 6-membered heterocycloalkyl. In certain embodiments, A is a 5- or 6-membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • A is pyrrolidinyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, thiomorpholinyl, morpholinyl, or piperazinyl.
  • A is piperidinyl. In other embodiments, A is
  • A is a 4-membered heterocycloalkyl.
  • R cl is hydrogen, alkyl, or cycloalkyl.
  • R cl is hydrogen, (C i- jalkyl, or (C3-C6)cycloalkyl.
  • R cl is hydrogen.
  • R cl is (Ci-C6)alkyl.
  • R cl is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R cl is (C3-C6)cycloalkyl.
  • R cl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NR C8 R c9 , -OR c1 °, and -S02R c11 , wherein each alkyl, cycloalkyl, and
  • heterocycloalkyl is independently unsubstituted or substituted with one or more halo.
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered haloheterocycloalkyl, -NO2, -CN, -SO2NH2, -NR C8 R c9 , -OH, -0-(Ci-C6)alkyl, -0-(Ci-C 6 )haloalkyl, and -S02R c11 .
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and -OH. In some embodiments, R c2 and R c3 are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, hexyl, halomethyl, haloethyl, halopropyl, halobutyl, halopentyl, halohexyl, -OH, methoxy, ethoxy, propoxy, and butoxy. In some embodiments, one of R c2 and R c3 is hydrogen. In some embodiments, R c2 and R c3 are both hydrogen.
  • R c2 and one R c4 together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R c2 and one R c4 together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R c2 and one R c4 together with the atoms to which they are attached, form a (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. In certain embodiments, the cycloalkyl is unsubstituted. In other embodiments, R c2 and one R c4 , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In certain embodiments, the heterocycloalkyl is unsubstituted.
  • R c2 and one R c4 together with the atoms to which they are attached, form a C3- cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • the cycloalkyl or heterocycloalkyl formed by R c2 and R c4 may be fused to ring A.
  • R c2 and R c4 may be fused to ring A.
  • R c3 is hydrogen.
  • R c3 and one R c4 together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R c3 and one R c4 together with the atoms to which they are attached, form a (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the cycloalkyl is unsubstituted. In other embodiments, R c3 and one R c4 , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the heterocycloalkyl is unsubstituted.
  • R c3 and one R c4 together with the atoms to which they are attached, form a C3- cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • the cycloalkyl or heterocycloalkyl formed by R c3 and R c4 may be fused to ring A.
  • R c3 and R c4 may be fused to ring A.
  • R c2 is hydrogen
  • R cl and one R c4 together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • the heterocycloalkyl is unsubstituted.
  • R cl and one R c4 together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R cl and one R c4 together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R c2 or R c3 is hydrogen. In other embodiments, both of R c2 and R c3 are hydrogen. In some embodiments, m is 0. Thus, in some embodiments,
  • R c2 and one R c4 together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein R c3 and one R c4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein R cl and one R c4 , together with the atoms to which they are attached, form a heterocycloalkyl; there may exist one or more other R c4
  • alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR c8 R c9 , -OR cl °, 0, -SR c51 , and -S0 2 R cl1 , wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently unsubstituted or substituted with one or more halo.
  • m is 3; R c2 and one R c4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining two R c4 are independently halo or alkyl.
  • m is 4; R c3 and one R c4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining three R c4 are independently -OH, halo, alkyl, or haloalkyl.
  • R c2 and R c3 together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or
  • heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R c2 and R c3 together with the atom to which they are attached, form a (C3- C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • the cycloalkyl is unsubstituted.
  • R c2 and R c3 together with the atom to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments the heterocycloalkyl is unsubstituted.
  • R cl and R c2 together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • the heterocycloalkyl is
  • R cl and R c2 together with the atom to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the
  • heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain.
  • alkyl as used herein has 1 to 50 carbon atoms ((Ci-C5o)alkyl), 1 to 20 carbon atoms ((Ci-C2o)alkyl), 1 to 12 carbon atoms ((Ci-Ci2)alkyl), 1 to 8 carbon atoms ((Ci-C8)alkyl), 1 to 6 carbon atoms ((Ci-C6)alkyl), or 1 to 4 carbon atoms ((Ci-C4)alkyl).
  • alkyl groups may, for example, include methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3- hexyl, and 3-methyl pentyl.
  • alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • butyl can include n-butyl, sec-butyl, isobutyl and t-butyl
  • propyl can include n-propyl and isopropyl.
  • Haloalkyl refers to an alkyl group substituted with one or more halo, which may be selected independently.
  • haloalkyl includes alkyl substituted with one or more halo independently selected from the group consisting of fluoro, chloro, iodo, and bromo.
  • Haloalkyl may include, for example, -CH2F, -CHF2, -CF3, -CH2CI, -CHCI2, -CCh, -CH2CHFCI, -CHFCH3, -CH 2 Br, and -CH 2 CHFCH 2 CH2Br.
  • alkenyl refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon double bond.
  • alkenyl as used herein has 2 to 50 carbon atoms ((C2-Cso)alkenyl), 2 to 20 carbon atoms ((C2-C2o)alkenyl), 2 to 12 carbon atoms ((C2-Ci2)alkenyl), 2 to 10 carbon atoms ((C 2 -Cio)alkenyl), 2 to 8 carbon atoms ((C2-C8)alkenyl), 2 to 6 carbon atoms ((C2-C6)alkenyl), or 2 to 4 carbon atoms ((C2- C4)alkenyl).
  • Alkenyl may have one, two, three, four, five, or more carbon-carbon double bonds, as valency permits. When an alkenyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • alkynyl refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon triple bond.
  • alkynyl as used herein has 2 to 50 carbon atoms ((C2-C5o)alkynyl), 2 to 20 carbon atoms ((C2-C2o)alkynyl), 2 to 12 carbon atoms ((C2-Ci2)alkynyl), 2 to 10 carbon atoms ((C2-Cio)alkynyl), 2 to 8 carbon atoms ((C2-C8)alkynyl), 2 to 6 carbon atoms ((C2-C6)alkynyl), or 2 to 4 carbon atoms ((C2- C4)alkynyl).
  • Alkynyl may have one, two, three, four, five, or more carbon-carbon triple bonds, as valency permits.
  • alkynyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • Cycloalkyl refers to a monocyclic or polycyclic saturated hydrocarbon.
  • cycloalkyl has 3 to 50 carbon atoms ((C3- C5o)cycloalkyl), 3 to 20 carbon atoms ((C3-C2o)cycloalkyl), 3 to 12 carbon atoms ((C3- Ci2)cycloalkyl), 3 to 8 carbon atoms ((C 3 -C8)cycloalkyl), 3 to 6 carbon atoms ((C 3 - C6)cycloalkyl), or 3 to 5 carbon atoms ((C 3 -C5)cycloalkyl).
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro- li/-indene, decahydronaphthalene, cubane, bicyclo[3. l.0]hexane, and bicyclof 1.1.1 jpentane.
  • Halocycloalkyl refers to a cycloalkyl group substituted with one or more halo, which may be selected independently.
  • halocycloalkyl includes cycloalkyl substituted with one or more halo independently selected from the group consisting of fluoro, chloro, iodo, and bromo.
  • Halocycloalkyl may include, for example, cyclopropyl substituted with two fluoro, cyclopropyl substituted with one fluoro and one chloro, cyclopentyl substituted with one fluoro, and cyclohexyl substituted with one bromo.
  • Aryl refers to a monocyclic or polycyclic group having at least one hydrocarbon aromatic ring, wherein all of the ring atoms of the at least one hydrocarbon aromatic ring are carbon. Wherein aryl includes a polycyclic system, no aromatic ring heteroatoms are present.
  • Aryl may include groups with a single aromatic ring (e.g ., phenyl) and multiple fused aromatic rings (e.g., naphthyl, anthryl).
  • Aryl may further include groups with one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (e.g., fluorenyl; 2,3-dihydro-lH-indene; 1,2,3,4-tetrahydronaphthalene).
  • aryl includes groups with an aromatic hydrocarbon ring fused to a non aromatic ring, wherein the non-aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S.
  • aryl includes groups with a phenyl ring fused to a non-aromatic ring, wherein the non-aromatic ring comprises at least one ring heteroatom independently selected from the group consisting ofN, O, and S (e.g., chromane; thiochromane; 2,3-dihydrobenzofuran; indoline).
  • aryl as used herein has from 6 to 14 carbon atoms ((C6- Ci4)aryl), or 6 to 10 carbon atoms ((C6-Cio)aryl). Where the aryl includes fused rings, the aryl may connect to one or more substituents or moieties of the formulae described herein through any atom for which valency permits.
  • “Fleteroaryl”, as used herein, refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S.
  • the heteroaryl group may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g., be a 5-membered, 6-membered, 7- membered, 8-membered, 9-membered, 10-membered, 11-membered, or l2-membered heteroaryl).
  • heteroaryl includes groups with an aromatic ring that comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S, (e.g., pyridinyl, pyrazinyl, furanyl, thiophenyl).
  • heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom, fused to a non-aromatic hydrocarbon ring (e.g., 5,6,7,8-tetrahydroquinolinyl; 4,5,6,7-tetrahydroisobenzofuranyl).
  • heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom fused to an aromatic hydrocarbon ring (e.g ., quinolinyl, quinoxalinyl, benzothiazolyl).
  • aromatic hydrocarbon ring e.g ., quinolinyl, quinoxalinyl, benzothiazolyl.
  • heteroaryl includes polycyclic groups with two fused aromatic rings, wherein each ring comprises at least one ring heteroatom (e.g., naphthyridinyl).
  • Heteroaryl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each ring heteroatom is independently selected from the group consisting of N, O, and S.
  • a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl.
  • Heterocycloalkyl refers to non-aromatic, monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S.
  • the heterocycloalkyl group may be saturated or unsaturated, and may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g., be a 3-membered, 4- membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10- membered, l l-membered, or l2-membered heterocycloalkyl).
  • Heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • a heterocycloalkyl has 2 to 8 ring carbon atoms and 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • heterocycloalkyl examples include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, and tropanyl.
  • Halo or“halogen” includes bromo, chloro, fluoro, and iodo.
  • substituted means a group wherein at least one hydrogen atom or electron pair is replaced by a bond to a non-hydrogen atom.
  • This may include, for example, a halogen atom such as F, Cl, Br, or I; an oxygen atom in a hydroxyl group; a nitrogen atom in an amino group; or an oxygen atom in a sulfur dioxide group.
  • “(Ci-C6)alkyl” (which may also be referred to as C1-C6 alkyl, Ci-6 alkyl, or Cl-6 alkyl) is intended to encompass Ci, C 2 , Cs, C 4 , Cs, Ce, Ci-6, Ci-s, CM, C M, CI- 2 , CM, CM, CM, CB-6, CS-S, C 3 -4, CM, CM, and C5-6 alkyl.
  • the compound of Formula (III) is a compound of Formula (III-A):
  • p is an integer from 0 to 7;
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7.
  • the compound of Formula (III) is a compound of Formula (III-B):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2- -S(0)r- -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7.
  • Z is aryl or heteroaryl. In some embodiments, Z is (C6-Cio)aryl. In certain embodiments, Z is 5- to 8- membered heteroaryl. In certain embodiments, Z is 5- to 7-membered heteroaryl. In some embodiments, Z is 5-, 6-, or 7-membered heteroaryl.
  • Z is 5- to 10-membered heteroaryl, wherein the heteroaryl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Z is 5- or 6-membered heteroaryl, wherein the heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Z is 9- or 10-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Z is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl.
  • Z is pyridazinyl, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, naphthyridinyl, or pyrrolyl.
  • Z is pyridazinyl, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, pur
  • Z is aryl.
  • Z is (C6-Cio)aryl, such as C6-aryl, (C7-Cio)bicyclic aryl, (Cs- Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl.
  • Z is phenyl or naphthyl.
  • Z is an aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring, for example (C7- Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring.
  • Z is:
  • Z is alkyl.
  • Z is (Ci-C6)alkyl.
  • Z is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • Z is propyl.
  • Z is cycloalkyl.
  • Z is (C3-Cio)cycloalkyl.
  • Z is (C5-Cio)cycloalkyl.
  • Z is (C5-C7)cycloalkyl.
  • Z is (C8-Cio)cycloalkyl.
  • Z is C3-cycloalkyl, C 4 - cycloalkyl, Cs-cycloalkyl, C6-cycloalkyl, C 7 -cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or Cio- cycloalkyl. In some embodiments, Z is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl.
  • Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tricyclooctyl.
  • Z is:
  • Z is heterocycloalkyl.
  • Z is 5- to 10-membered heteroaryl, or 5- to 10- membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Z is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Z is 9- or 10-membered bicyclic heteroaryl comprising one to three ring heteroatoms
  • Z is a 5- membered heteroaryl.
  • Z is pyrazolyl, thiophenyl, furanyl, or oxazolyl.
  • Z is a 9-membered heteroaryl.
  • Z is benzothiophenyl or indolyl.
  • Z is a 6-membered heteroaryl.
  • Z is alkyl or cycloalkyl.
  • Z is hydrogen.
  • Z is alkyl.
  • Z is cycloalkyl.
  • Z is aryl.
  • Z is 6- to 10-membered heteroaryl.
  • Z is 5-membered heteroaryl comprising two or more annular N atoms.
  • Z is or 5-membered heteroaryl comprising at least one annular O or S atom.
  • Z is , as
  • v is an integer from 0 to 5.
  • Z is N "NH as described above, and ( R ° ⁇ is N 'NH ; wherein v is an
  • v is an integer from 0 to 11.
  • v is an integer from 0 to 10, or from 0 to 8, or from 0 to 6, or from 1 to 11, or from 1 to 9, or from 1 to 7, or from 2 to 11, or from 2 to 9, or from 2 to 7, or from 2 to 5, or from 3 to 11, or from 3 to 9, or from 3 to 7, or from 3 to 5.
  • v is an integer from 0 to 5.
  • v is an integer from 0 to 4.
  • v is an integer from 0 to 3.
  • v is 0, 1, or 2. In other embodiments, v is an integer from 1 to 6, or from 2 to 6, or from 3 to 6, or from 3 to 5, or from 2 to 4. In certain embodiments, v is 0. In other embodiments, v is 1 In some embodiments, v is 2. In still other embodiments, v is 3. In still further embodiments, v is 4. In some embodiments, v is 5. In certain embodiments, v is 6.
  • Z is hydrogen and v is 0.
  • Z is phenyl
  • v is an integer from 0 to 5.
  • Z is phenyl
  • v is an integer from 0 to 5.
  • the compound of Formula (III) is a compound of Formula (III-A-ii):
  • p is an integer from 0 to 7;
  • d is an integer from 0 to 5;
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
  • the compound of Formula (III) is a compound of Formula (III-B-ii):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2- -S(0)r- -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • d is an integer from 0 to 5;
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
  • Y is -C(R c49 )2-, wherein each R c49 is independently hydrogen or R c4 .
  • Y is -CH2-.
  • Y is -CHR c4 -.
  • Y is -C(R c4 )2-
  • Y is -S(0)r-, where r is 0, 1, or 2.
  • Y is -S-.
  • Y is -S(O)-
  • Y is -S(0)2- In some
  • Y is -0- In other embodiments, Y is -N(R c49 )-, wherein R c49 is hydrogen or R c4 .
  • R c49 is hydrogen or R c4 .
  • Y is -NH-. In some embodiments, Y is -NR c4 -.
  • B is heteroaryl, cycloalkyl, or heterocycloalkyl.
  • B is 5- to lO-membered heteroaryl, or 5- to lO-membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 9- or 10- membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is heterocycloalkyl.
  • B is 3- to lO-membered heterocycloalkyl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 5- to 10- membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 5- or 6-membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 9- or lO-membered
  • heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is a 5,5-ring fused
  • B is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or tropanyl.
  • B is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or tropanyl.
  • B is heteroaryl.
  • B is 5- to 10- membered heteroaryl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 9- or lO-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 9- or 10-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl. In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (IP-B), or Formula (III-B-ii), or a stereoisomer or
  • B is pyridazinyl, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl,
  • B is:
  • B is aryl.
  • B is (C6-Cio)aryl, such as C6-aryl, (C7-Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl.
  • B is phenyl or napthyl.
  • B is an aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring, for example (C7-Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring.
  • B is:
  • B is cycloalkyl
  • B is (C3-Cio)cycloalkyl. In certain embodiments, B is (C5-Cio)cycloalkyl. In other embodiments, B is (C5-C7)cycloalkyl. In still other embodiments, B is (Ce- Cio)cycloalkyl. In some embodiments, B is C3-cycloalkyl, C 4 -cycloalkyl, Cs-cycloalkyl, C6- cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or Cio-cycloalkyl.
  • B is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl.
  • B is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl.
  • B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tri cyclooctyl.
  • B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tri cyclooctyl.
  • B may be unsubstituted or substituted with one to eleven R c5 as described in Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), as valency allows.
  • R c5 For ( B)-(R c5 )
  • B is as described above, and IS , wherein n is an integer from 0 to 5.
  • B is , as described above, and is , wherein n is an integer from 0 to 11.
  • n is an integer from 0 to 11. In some embodiments, n is an integer from 0 to 9. In other embodiments, n is an integer from 0 to 7. In still further embodiments, n is an integer from 0 to 5. In certain embodiments, n is an integer from 0 to 3. In other embodiments, n is an integer from 3 to 11, or from 5 to 11, or from 7 to 11, or from 3 to 7, or from 3 to 5. In certain embodiments, n is 0. In other embodiments, n is 1.
  • n is 2. In still other embodiments, n is 3. In still further embodiments, n is 4. [0088] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is phenyl, and n is an integer from 0 to 5. Thus, for example, in some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof,
  • the compound of Formula (III) is a compound of Formula (III-A-i):
  • p is an integer from 0 to 7;
  • d is an integer from 0 to 5;
  • R c4 , R c5 , and R c6 are as defined for Formula (III).
  • the compound of Formula (III) is a compound of Formula (III-A-iii):
  • p is an integer from 0 to 7;
  • d is an integer from 0 to 5;
  • R c4 , R c5 , and R c6 are as defined for Formula (III).
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
  • the compound of Formula (III) is a compound of Formula (III-B-iii):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2-, -S(0) I -, -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • d is an integer from 0 to 5;
  • the compound of Formula (III) is a compound of Formula (III-B-i):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2-— S(0)— , -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • d is an integer from 0 to 5;
  • R c4 , R c5 , and R c6 are as defined for Formula (III).
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
  • Y is -C(R c49 ) 2- , wherein each R c49 is independently hydrogen or R c4 .
  • Y is -CH2-.
  • Y is -CHR c4 -.
  • Y is -C(R c4 )2-
  • Y is -S(0)r-, where r is 0, 1, or 2.
  • Y is -S-.
  • Y is -S(O)-.
  • Y is -S(0)2- In some embodiments, Y is -0- In other embodiments, Y is -N(R c49 )-, wherein R c49 is hydrogen or R c4 .
  • R c49 is hydrogen or R c4 .
  • Y is -NH-. In some embodiments, Y is -NR c4 -.
  • d is an integer from 0 to 5. In other embodiments, d is an integer from 0 to 4, or from 0 to 3, or from 0 to 2. In some embodiments,
  • d is 0 or 1. In certain embodiments, d is 1. In other embodiments, d is 2. In some embodiments, d is 3. In still other embodiments, d is 4. In certain embodiments, d is 5.
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl.
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C3- C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, or 3- to lO-membered
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, (Ci-C6)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocycloalkyl.
  • each R c4 is independently selected from the group consisting of fluoro, chloro, bromo, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3- C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to 6-membered heterocycloalkyl, -NO2, -CN, -SO2NH2, -NH2, - H(Ci-C6)alkyl, -N((Ci-C 6 )alkyl)((Ci-C6)alkyl), -OH, -0-(Ci-C 6 )alkyl
  • each R c4 is independently selected from the group consisting of fluoro, chloro, bromo, (Ci-C6)alkyl, (Ci- C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl.
  • At least one R c4 is fluoro, chloro, bromo, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, or -0-(Ci- C6)haloalkyl.
  • at least one R c4 is fluoro, chloro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH 2 F, -CHF2, or -CF3.
  • two to four R c4 together with the atoms to which they are attached, form a (C6- Cio)aryl, 3- to 6-membered heteroaryl, (C3-C6)cycloalkyl, or 3- to 6-membered
  • heterocycloalkyl wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is
  • the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted.
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is fused with ring A.
  • the cycloalkyl or heterocycloalkyl forms a spirocyclic system with ring A.
  • each R c6 is independently selected from the group consisting of halo, alkyl, haloalkyl, -OR c27 , and -NR c28 R c29 , wherein each R c27 , R c28 , and R c29 is independently hydrogen, alkyl, or haloalkyl.
  • each R c6 is independently halo, (Ci-C6)alkyl, (Ci- C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, or -NR c28 R c29 , wherein R c28 and R c29 are independently hydrogen, (Ci-C6)alkyl, or (Ci-C6)haloalkyl.
  • At least one R c6 is chloro, fluoro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF 3 , -CH 2 F, -CHF2, -CF3, -ML ⁇ , -MI(CH 3 ), -N(CH 3 ) 2 ,
  • each R c6 is independently chloro, fluoro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF 3 , -CH 2 F, -CHF2, -CF 3 , -ML ⁇ , -MI(CH 3 ), -N(CH 3 ) 2 ,
  • each R c6 is independently fluoro, chloro, methoxy, methyl, -CF 3 , -OH, or -N(CH 3 )2. In some embodiments, at least one R c6 is chloro, fluoro, methoxy, methyl, -OH, -CF 3 , or -N(CH 3 ) 2 .
  • each R c5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, NO2, CN, S02NR c52 R c53 ,
  • one or more R c5 is independently selected from the group consisting of halo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl; heterocycloalkyl;
  • one or more R c5 is independently selected from the group consisting of halo, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl.
  • each R c5 is independently selected from the group consisting of halo, (Ci- C6)alkyl, (Ci-Ce)haloalkyl, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, and -CN.
  • one or more R c5 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH 3 )2,
  • At least one R c5 is halo, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, or -CN. In certain embodiments, at least one R c5 is chloro, fluoro, -OCH3, -OCH2CH3, -OCH(CH 3 )2, -CH2F, -CHF2, -CF3, -OCH2F,
  • At least one R c5 is chloro, fluoro, -OCH3, or -CN. In some embodiments, each R c5 is independently chloro, fluoro, -OCH3, or -CN.
  • each R c62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • the alkyl is (Ci-Ci2)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In other embodiments, the alkyl is (Ci-Cs)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In further embodiments, the alkyl is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In still other embodiments, the alkyl is (Ci-C4)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In some embodiments, at least one R c5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, difluoromethyl, or fluoromethyl.
  • each R c23 is independently (Ci-C6)alkyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R c23 is unsubstituted alkyl. In some embodiments, R c23 is unsubstituted (Ci- C6)alkyl.
  • R c23 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
  • each R c23 is independently (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, 3- to 8- membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • at least one R c5 is unsubstituted cycloalkyl.
  • At least one R c5 is unsubstituted (C3-C6)cycloalkyl. In some embodiments, at least one R c5 is cycloalkyl substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
  • each R c23 is independently (Ci-C6)alkyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R c23 is unsubstituted (Ci-C6)alkyl.
  • at least one R c5 is unsubstituted aryl.
  • each R c23 is independently (Ci-C6)alkyl, (C3- C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R c23 is unsubstituted (Ci-C6)alkyl.
  • at least one R c5 is unsubstituted heteroaryl.
  • each R c23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R c23 is independently (Ci-C6)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (Cr > - Cio)aryl, or 3- to 8-membered heteroaryl.
  • R c23 is unsubstituted (Ci-C6)alkyl.
  • at least one R c5 is unsubstituted heterocycloalkyl.
  • RCSS R c54 R CS5 ; R C56 R C5T R CS8 > R C59 R C6O and RC6i independently hydrogen, (C 1 -C 6 )alkyl,
  • heterocycloalkyl (C6-Cio)aryl, 3- to lO-membered heteroaryl, (C2-C6)alkynyl, or (C2- C6)haloalkynyl.
  • each R cl5 , R cl6 , R cl7 , R cl8 , R cl9 , R c52 , R c53 , R c54 , R c55 , R c56 , R c57 , R c58 , R c59 , R c60 , and R c61 is independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C 3 -C6)cycloalkyl, and (C 3 -C6)halocycloalkyl.
  • each R ci2, ⁇ c 13 RC 2O C2 I ⁇ an d R c22 independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl.
  • each R cl2 , R cl3 , R c20 , R c21 , and R c22 is
  • each R cl4 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl. In certain embodiments, each R cl4 is independently hydrogen, (Ci-C6)alkyl, (C3- C6)cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-Cio)aryl, 3- to lO-membered heteroaryl, or (C3-C6)alkynyl.
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R cl2 , R cl3 , R cl4 , R cl7 , R cl8 , R cl9 , R c20 , R c21 , R c22 , and R c23 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R c62 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, 0,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
  • alkyl independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo,
  • -CN, -SFs, 0, -NR C40 R c41 , -NR C42 C(0)R c43 , -OR c44 , and R c63 ;
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R cl2 , R cl3 , R cl4 , R cl7 , R cl8 , R cl9 , R c20 , R c21 , R c22 , and R c23 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R c62 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, 0, -CN, (C6-Cio)aryl, 5- to lO-membered heteroaryl, (Ci-Ce)alkyl, (C2-Ce)alkynyl, (C3- C6)cycloalkyl, 5- to 10-membered heterocycloalkyl, -NR c24 R c25 , -
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
  • alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, 0, -NR C40 R c41 , -NR C42 C(0)R c43 , -OR c44 , and R c63 ;
  • each R c24 , R c25 , R c26 , R c40 , R c41 , R c42 , R c43 , and R c44 is independently hydrogen, alkyl, or haloalkyl.
  • each R c24 , R c25 , R c26 , R c40 , R c41 , R c42 , R c43 , and R c44 is independently hydrogen, (C i-Cr,)alkyh or (Ci-C6)haloalkyl
  • At least one R c5 is:
  • R c30 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R c31 and R c32 is independently hydrogen, halo, or alkyl
  • each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR c37 , and -NR c38 R c39 ;
  • each R c33 , R c34 , R c35 , R c36 , R c37 , R c38 , R c39 , R c45 , R c46 , R c47 , and R c48 is independently hydrogen, alkyl, or haloalkyl;
  • each R c33 , R c34 , R c35 , R c36 , R c37 , R c3S , R c39 , R c45 , R c46 , R c47 , and R c48 is independently hydrogen, (Ci-C6)alkyl, or (Ci-C6)haloalkyl.
  • each R c33 , R c34 , R c35 , R c36 , R c37 , R c38 , R c39 , R c45 , R c46 , R c47 , and R c48 is independently hydrogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, or halobutyl.
  • R c30 is hydrogen.
  • substituents independently selected from the group consisting of halo, -SFs, (C3
  • R c30 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with one or more (C6-Cio)aryl or 3- to 6-membered heteroaryl.
  • R c30 is unsubstituted (Ci-C6)alkyl. In other embodiments, R c30 is (Ci-C6)alkyl substituted with 3- to 6-membered heteroaryl. In other embodiments, R c30 is (Ci-C6)alkyl substituted with phenyl, wherein the phenyl is unsubstituted or substituted with one more substituents independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkynyl, (Ci-C 6 )haloalkyl, -OH, -0(Ci-Ce)alkyl, -SFs, -NHC(0)H, and -NHC(O)- (Ci-C6)alkyl.
  • R c30 is (Ci-C6)alkyl substituted with (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci- C6)alkyl.
  • R c30 is (Ci-Ce)alkyl substituted with 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C6)alkyl.
  • R c30 is (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C6)alkyl.
  • R c30 is 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C6)alkyl.
  • R c30 is 3- to lO-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C6)alkyl.
  • R c30 is alkynyl. In certain embodiments, R c30 is (C2- C6)alkynyl.
  • R c is
  • R c30 is:
  • R c31 and R c32 attached to the same carbon form a cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • the cycloalkyl is a (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • R c31 and R c32 attached to the same carbon form an unsubstituted cyclopropyl or cyclobutyl.
  • R c31 and R c32 attached to the same carbon form a cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl are substituted with one or more halo.
  • each R c31 and R c32 is hydrogen.
  • At least one R c31 or one R c32 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, aryl, 3- to 6-membered heteroaryl, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -Nth, -NH(Ci-C6)alkyl, -N((Ci- C6)alkyl)((Ci-C6)alkyl).
  • one R c31 or one R c32 is (Ci-Ce)alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, and -OH.
  • one R c31 or one R c32 is (C i-Cr,)alkyl, wherein the alkyl is unsubstituted or substituted with fluoro, chloro, (C3-C6)cycloalkyl, (C3)halocycloalkyl, or -OH.
  • one R c31 or one R c32 is ethyl substituted with difluorocy cl opropy 1.
  • the 4- to lO-membered heterocycloalkyl is a polycyclic heterocycloalkyl.
  • at least one R c31 or R c32 is alkyl substituted with 5- to 6-membered heteroaryl.
  • q is 1. In still other embodiments, q is 2. In some embodiments, q is 1, and one of R c31 and R c32 is hydrogen. In some embodiments, q is 1 and R c31 is hydrogen. In other embodiments, q is 2, and one R c31 and two R c32 are hydrogen. In other embodiments, q is 2, and two R c31 and one R c32 are hydrogen. In some embodiments, q is 2, and two R c31 and three R c32 are hydrogen. In some embodiments, q is 2, and three R c31 and two R c32 are hydrogen.
  • X is -S(O)-, -S(0) 2- , -S(0)NR c50 -, -C(S)-, -C(O)-, or -C(R c7 ) 2-
  • X is -S(0) 2- , -C(O)-, or -C(R c7 ) 2-.
  • X is -S(O)-,
  • X is -C(S)-, -C(O)-, or -C(R c7 ) 2- .
  • X is -S(O)-.
  • X is -S(0) 2-
  • R c50 is hydrogen.
  • R c50 is unsubstituted (Ci-C6)alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • X is -C(S)-.
  • X is -C(O)-.
  • X is -C(R c7 ) 2- , wherein each R c7 is independently hydrogen, halo, alkyl, or haloalkyl. In certain embodiments, each R c7 is independently hydrogen, halo, (Ci-C6)alkyl, or (Ci-C6)haloalkyl.
  • each R c7 is independently hydrogen, chloro, fluoro, methyl, ethyl, propyl, -CFkF, -CHF2, or -CF3. In some embodiments, each R c7 is H, and X is -CH2-.
  • X is -S(0) 2- , -C(O)-, or -CH2-.
  • the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii) is:
  • the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii) is:
  • the compounds described herein including compounds of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (PI-B), Formula (III-B-i), Formula (III-B-ii), or Formula (IP-B-iii), or their stereoisomers or pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, or other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( R )- or (5)-.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), or ( R )- and (ri)-i somers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid
  • “Pharmaceutically acceptable salt” includes a salt which is generally safe, non toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. Such salts may include acid addition salts and base addition salts.
  • Acid addition salts may be formed with inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid
  • Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, pur
  • the compounds provided herein including compounds of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or their stereoisomers or pharmaceutically acceptable salts, also include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds may have the present structures except for the replacement of a hydrogen by a deuterium (D or 2 H) or tritium ( 3 H), or the replacement of a carbon-l2 by a carbon-l3 ( 13 C) or carbon-l4 ( 14 C).
  • the compounds disclosed herein such as a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (PI-B), Formula (III-B-i), Formula (III-B-ii), or Formula (IP-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, may be prepared, for example, through the reaction route depicted in General Scheme III- 1.
  • General Scheme III-l provides one route to prepare a compound disclosed herein, such as a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B- iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • compound PI-102 is combined with 2-cyanoacetic acid (compound III-104), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC HCI),
  • compound III-110 This mixture is stirred at room temperature for 4 hours to produce compound III-110.
  • This compound is then combined with piperidine (30 mol%), a solvent (such as dimethylsulfoxide, DMSO), and R z -C(0)H, wherein R z is hydrogen or substituted or unsubstituted alkyl, cycloalkyl, aryl, or heteroaryl, and this mixture stirred at 100 °C for 18 h to produce compound III-112, which is an example of a compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
  • a pharmaceutical composition comprising a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient may include, for example, an adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans.
  • Pharmaceutically acceptable excipients may include, but are not limited to, water, NaCl, normal saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors.
  • kits for treating a disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (III), Formula (TTT-A) Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
  • a pharmaceutical composition comprising a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
  • the compound administered to the subject in need thereof according to the methods described herein is a compound described in an embodiment, example, figure, or table herein, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • Also provided herein is the use of a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
  • the disorder is related to K-Ras, for example a disorder associated with a mutation of K-Ras or
  • the disorder is related to the KRAS gene, for example a disorder associated with a mutation of the KRAS gene or dysregulation of the KRAS gene. Mutation or dysregulation of K-Ras or KRAS may include mutation or dysregulation of human K-Ras4a and/or human K-Ras4b. In some embodiments, the disorder is related to the K-Ras (for example, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, for example a disorder related to aberrant K-Ras signaling pathway activity. In some embodiments, the disorder is related to a mutation or dysregulation of human K-Ras4b. In certain embodiments, the disorder is related to aberrant K-Ras4b signaling pathway activity.
  • K-Ras4as for example, human K-Ras4a and/or human K-Ras4b
  • the disorder is related to a mutation or dysregulation of human K-Ras4b. In certain embodiments, the
  • the disorder is neurofibromatosis type 1 (NF1), Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • the disorder is neurofibromatosis type 1 (NF 1 ).
  • NF1 is a disorder that predisposes subjects to cancer. Subjects with NF1 are at greater risk than the general population for developing malignancies, which may include pediatric malignancies or adult malignancies. Pediatric malignancies may include optic pathway glioma, rhabdomyosarcoma, neuroblastoma, and juvenile myelomonocytic leukemia.
  • Adult malignancies may include malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas,
  • the disorder is cancer.
  • the cancer is related to K-Ras, for example a cancer associated with a mutation of K-Ras or dysregulation of K-Ras.
  • the cancer is related to the KRAS gene, for example a cancer associated with a mutation of the KRAS gene or dysregulation of the KRAS gene.
  • Mutation or dysregulation of K-Ras or KRAS may include mutation or dysregulation of human K-Ras4a and/or human K-Ras4b.
  • the cancer is related to the K-Ras (for example, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, for example cancer related to aberrant K-Ras signaling pathway activity.
  • the cancer is related to mutation or dysregulation of human K-Ras4b.
  • the cancer is related to aberrant K-Ras4b signaling pathway activity.
  • the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (IP-A- ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • the cancer is breast cancer. In other embodiments, the cancer is pancreatic cancer. In still further embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is lung cancer. In some embodiments, the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III- B), Formula (III-B-i), Formula (III-B-ii), or Formula (PI-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, is co-administered with one or more
  • chemotherapeutic agents to a subject in need thereof.
  • a method of reducing the level of a K-Ras protein in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (III), Formula (III-A), Formula (III-A-i),
  • the K-Ras protein is human K-Ras4a and/or human K-Ras4b.
  • the K- Ras is human K-Ras4b. Reduction of the level of K-Ras may be evaluated, for example, by immunoblot of a biological sample using one or more specific anti-K-Ras antibodies, or by mass spectrometry-based methods.
  • administering a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, to a subject may block one or more post-translational processing steps of a K-Ras precursor (such as K-Ras4a precursor or K-Ras4b precursor). This unprocessed precursor may then be degraded by the body, thus reducing the level of K-Ras protein.
  • K-Ras precursor such as K-Ras4a precursor or K-Ras4b precursor
  • the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof covalently binds to the C185 amino acid residue of a K-Ras precursor (such as K-Ras4a precursor or K- Ras4b precursor) to block one or more post-translational modifications.
  • a K-Ras precursor such as K-Ras4a precursor or K- Ras4b precursor
  • the post-translational modification that is blocked is farnesylation.
  • a method of reducing the activity of a K-Ras protein in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (III), Formula (III-A), Formula (III-A-i),
  • the K-Ras protein is human K-Ras4a and/or human K-Ras4b.
  • the K-Ras is human K-Ras4b.
  • both the activity of K-Ras and the level of K-Ras are reduced in a subject in need thereof.
  • Effective amount or“therapeutically effective amount” refer to that amount of a compound of the disclosure that, when administered to a mammal, for example a human, is sufficient to effect treatment.
  • the amount of a compound of the disclosure which constitutes a“therapeutically effective amount” may vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated.
  • the terms“treat,” “treating,” or “treatment” refer to any indicia of success in the amelioration of an injury, disease, disorder, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, disorder, pathology, or condition more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of injury, disease, disorder, pathology, or condition; making the final point of degeneration less debilitating; improving a subject’s physical or mental well-being; or relieving or causing regression of the injury, disease, disorder, pathology, or condition.
  • the treatment of symptoms can be based on objective or subjective parameters, which may include the results of a physical examination, a neuropsychiatric exam, and/or a psychiatric evaluation.
  • Certain methods disclosed herein may treat cancer by, for example, decreasing the incidence of cancer, causing remission of cancer, slowing the rate of growth of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis, reducing the growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combinations thereof.
  • Co-administer includes administering a compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or composition comprising any of these as described herein at the same time, just prior to, or just after the administration of one or more additional therapies, such as a chemotherapeutic agent.
  • additional therapies such as a chemotherapeutic agent.
  • One or more compounds or salts thereof disclosed herein and one or more additional therapies may be co-administered as a single combination form, or may be co-administered as two or more separate forms simultaneously or sequentially.
  • Embodiment I- 1 A compound of Formula (III):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
  • A is piperidinyl and B is phenyl or thiophenyl
  • Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
  • X is -S(O)-, -S(0)2-, -S(0)NR c50 -, -C(S)-, -C(O)-, or -C(R c7 ) 2- ;
  • each R c7 is independently hydrogen, halo, alkyl, or haloalkyl
  • R cl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NR c8 R c9 , -OR cl °, and -S02R c11 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each R c4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCh, -CN, -SO2NH2, -NR C8 R c9 , -OR c1 °, 0, -SR c51 , and -SCkR c11 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl
  • R c4 together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R c2 and one R c4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R c2 and R c3 together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
  • each R c5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R c23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R c62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R c54 , R c55 , R c56 , R c57 , R c58 , R c59 , R c60 , and R c61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R cl2 ,
  • RGB R C R C P R C18 ⁇ R CW R C20 5 R C2 1 R c22 and R c23 ⁇ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R c62 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • n is an integer from 0 to 11;
  • Embodiment 1-2 The compound of Embodiment 1-1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Z is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl
  • A is piperidinyl and B is phenyl or thiophenyl
  • Z is hydrogen, alkyl, cycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
  • X is -S(O)-, -S(0) 2- - S(0)NR c50 -, -C(S)-, -C(O)-, or -C(R c7 ) 2- ;
  • each R c7 is independently hydrogen, halo, alkyl, or haloalkyl
  • R cl is hydrogen, alkyl, or cycloalkyl
  • R c2 and R c3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR c8 R c9 , -OR cl °, and -S02R c11 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R c4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR C8 R c9 , -OR c1 °, 0, -SR c51 , and -S02R c11 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is independently unsubstituted or substituted with one or more halo;
  • each R c8 , R c9 , R cl °, R cl1 , and R c51 is independently hydrogen, alkyl, haloalkyl,
  • R c4 together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or R c2 and one R c4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl;
  • R c2 and R c3 together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl;
  • each R c5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R c62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R cS0 , and R c61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
  • each R cl2 , R cl3 , R c20 , R c21 , and R c22 is independently hydrogen, alkyl
  • each R cl4 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
  • heterocycloalkyl, aryl, or heteroaryl of R c62 is independently unsubstituted or substituted with one or more substituents
  • halo 0, CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • each R c24 , R c25 , R c26 , R c40 , R c41 , R c42 , R c43 , and R c44 is independently hydrogen, alkyl, or haloalkyl;
  • each R c6 is independently selected from the group consisting of halo, alkyl, haloalkyl, OR c27 , and NR c28 R c29 , wherein each R c27 , R c28 , and R c29 is independently hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • v is an integer from 0 to 11.
  • Embodiment 1-3 The compound of Embodiment 1-1 or 1-2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is aryl or heteroaryl.
  • Embodiment 1-4 The compound of any one of Embodiments 1-1 to 1-3, wherein the compound is of Formula (III-A):
  • p is an integer from 0 to 7;
  • Embodiment 1-5 The compound of any one of Embodiments 1-1 to 1-4, wherein the compound is of Formula (III-A-ii):
  • p is an integer from 0 to 7;
  • d is an integer from 0 to 5;
  • Embodiment 1-6 The compound of any one of Embodiments 1-1 to 1-3, wherein the compound is of Formula (III-B):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2- -S(0)r- -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • Embodiment 1-7 The compound of any one of Embodiments 1-1 to 1-3, or 1-6, wherein the compound is of Formula (III-B-ii):
  • p is an integer from 0 to 7;
  • Y is -C(R c49 ) 2- , -S(0)r- -O-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • d is an integer from 0 to 5;
  • Embodiment 1-8 The compound of Embodiment 1-6 or 1-7, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CH2-.
  • Embodiment 1-9 The compound of any one of Embodiments 1-1 to 1-3, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
  • Embodiment 1-10 The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment 1-11 The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment 1-12 The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C9-Cio)bicyclic aryl.
  • Embodiment 1-13 The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C5-Cio)cycloalkyl.
  • Embodiment 1-14 The compound of any one of Embodiments 1-1 to 1-13, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one or more R c5 is independently selected from the group consisting of halo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl; heterocycloalkyl;
  • Embodiment 1-15 The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
  • Embodiment 1-16 The compound of any one of Embodiments 1-1 to 1-4, 1-6, or I- 9 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 5- membered heteroaryl.
  • Embodiment 1-17 The compound of Embodiment 1-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is pyrazolyl, thiophenyl, furanyl, or oxazolyl.
  • Embodiment 1-18 The compound of any one of Embodiments 1-1 to 1-4, 1-6, or I- 8 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 9- membered heteroaryl.
  • Embodiment 1-19 The compound of Embodiment 1-18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is benzothiophenyl or indolyl.
  • Embodiment 1-20 The compound of any one of Embodiments 1-1 to 1-4, 1-6, or I- 8 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 6- membered heteroaryl.
  • Embodiment 1-21 The compound of any one of Embodiments 1-1, 1-2, 1-4, 1-6, or 1-8 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is alkyl or cycloalkyl.
  • Embodiment 1-22 The compound of any one of Embodiments 1-1 to 1-5, 1-9, or I- 14, wherein the compound is of Formula (III-A-i):
  • p is an integer from 0 to 7;
  • d is an integer from 0 to 5; and X, R c4 , R c5 , and R c6 are as defined for Formula (III).
  • Embodiment 1-2 The compound of Embodiments 1-1 to 1-3, 1-6 to 1-9, or 1-14, wherein the compound is of Formula (III-B-i):
  • p is an integer from 0 to 7;
  • Y is -C(R c49 ) 2 -,— S(0)— , -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • d is an integer from 0 to 5;
  • R c4 , R c5 , and R c6 are as defined for Formula (III).
  • Embodiment 1-24 The compound of any one of Embodiments 1-1 to 1-5, 1-9, or I- 14, wherein the compound is of Formula (III-A-iii):
  • p is an integer from 0 to 7;
  • d is an integer from 0 to 5;
  • Embodiment 1-25 The compound of Embodiments 1-1 to 1-3, 1-6 to 1-9, or 1-14, wherein the compound is of Formula (III-B-iii):
  • p is an integer from 0 to 7;
  • Y is -C(R C49 )2-,— S(0)— , -0-, or -N(R c49 )-, wherein each R c49 is independently hydrogen or R c4 ;
  • r 0, 1, or 2;
  • d is an integer from 0 to 5;
  • R c4 , R c5 , and R c6 are as defined for Formula (III).
  • Embodiment 1-26 The compound of any one of Embodiments 1-1 to 1-25, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R c5 is:
  • R c30 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R c31 and R c32 is independently hydrogen, halo, or alkyl
  • each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR c37 , and _ NR C38 R c39 ;
  • each R c33 , R c34 , R c35 , R c36 , R c37 , R c38 , R c39 , R c45 , R c46 , R c47 , and R c48 is independently hydrogen, alkyl, or haloalkyl;
  • Embodiment 1-27 The compound of Embodiment 1-26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and R c31 is hydrogen.
  • Embodiment 1-2 The compound of Embodiment 1-28, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R c23 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
  • Embodiment 1-30 The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
  • Embodiment 1-3 The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • Embodiment 1-3 The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CH 2-
  • Embodiment 1-33 The compound of any one of Embodiments 1-1 to 1-21 or 1-26 to 1-32, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  • Embodiment 1-34 The compound of any one of Embodiments 1-1 to 1-3, 1-9 to I- 21, or 1-26 to 1-32, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
  • Embodiment 1-35 The compound of any one of Embodiments 1-4 to 1-8, or 1-22 to 1-25, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.
  • Embodiment 1-36 The compound of any one of Embodiments 1-1 to 1-35, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R c6 is chloro, fluoro, methoxy, methyl, -OH, -CF 3 , or -N(CH3)2.
  • Embodiment 1-37 The compound of Embodiment 1-1, wherein the compound is:
  • Embodiment 1-38 A pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-39 A method of reducing the level of a K-Ras protein in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-40 The method of Embodiment 1-39, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-4 A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-42 The method of Embodiment 1-41, wherein the disorder is cancer.
  • Embodiment 1-43. The method of Embodiment 1-42, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • Embodiment 1-44 The method of Embodiment 1-41, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-45 The method of any one of Embodiments 1-41 to 1-44, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment 1-46 Use of a compound of any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof.
  • Embodiment 1-47 The use of Embodiment 1-46, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-48 Use of a compound of any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
  • Embodiment 1-49 The use of Embodiment 1-48, wherein the disorder is cancer.
  • Embodiment 1-50 The use of Embodiment 1-49, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • Embodiment 1-51 The use of Embodiment 1-48, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-52 The use of any one of Embodiments 1-48 to 1-51, wherein the cancer is associated with a mutation of K-Ras.
  • Embodiment 1-53 A compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
  • Embodiment 1-54 The compound for use of Embodiment 1-53, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-55 A compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
  • Embodiment 1-56 The compound for use of Embodiment 1-55, wherein the disorder is cancer
  • Embodiment 1-57 The compound for use of Embodiment 1-56, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma,
  • rhabdomyosarcoma neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • Embodiment 1-58 The compound for use of Embodiment 1-55, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-59 The compound for use of any one of Embodiments 1-55 to 1-58, wherein the cancer is associated with a mutation of K-Ras.
  • Example III-l Synthesis of tert-butyl (R)-3-((2-cyanoacetamido)methyl)piperidine-l- carboxylate
  • Example III-3 Synthesis of (R,E)-N-((l-(5-chloro-2-methoxybenzoyl)piperidin-3- yl)methyl)-2-cyano-3-(4-methoxyphenyl)acrylamide
  • Target plate pretreatment Before each assay, the MALDI target plate (Bruker MTP 384 ground steel BC) is pre-treated by pipetting 1 m ⁇ of saturated sinapinic acid in acetonitrile (ACN) onto each spot. This may improve the uniformity of sample crystallization across the plate, enhancing sensitivity.
  • ACN acetonitrile
  • Measurements MALDI-TOF measurements are performed on a Bruker Daltonics ultraflex III TOF-TOF mass spectrometer using linear mode and mass range from 5 to 45 kDa. Detector gain is set to x 9 (1734 V), sample rate to 1 GS/s, smart beam parameter set: 3_medium is used, and the laser frequency is 66.7 Hz. Spectra are automatically collected using a custom AutoXecute method. Laser power is auto-adjusted using fuzzy control. The peak selection range is set to be between 20500 and 23000 Da. Peak evaluation uses half width parameter set to be smaller than 30 Da. Fuzzy control uses Proteins/Oligonucleotides protocol with minimum half width 1/6 times above threshold. Up to 1500 shots are collected in 500 shot steps. Dynamic termination is implemented to finish data collection when peak intensity is reaching value of 1200 [a.u.].
  • Spectra processing Spectra are smoothed by SavitzkyGolay algorithm using 12 m/z width and six cycles. Centroid peak detection algorithm is used with signal to noise threshold set to 11, relative intensity threshold 5%, minimum intensity threshold 50 [a.u.], peak width 20 m/z and TopHat baseline subtraction. Peak intensity and area under the peak are evaluated and recorded for all peaks between 21,460 Da and 23,500 Da.
  • MEF mouse embryonic fibroblast
  • K-Ras4b G12D, K-Ras4b G12V, K-Ras4b Q61R, H-Ras WT The control cell line is KRAS G12D MEF that carries C185S mutation (preventing posttranslational modification by farnesyl), and membrane attachment that is necessary for K-Ras signaling is enabled through N-terminal myristoyl moiety (Myr-K-Ras G12D/C185S). Cell viability in the presence of synthesized compounds is measured using CellTiter-Glo® (Promega).
  • Cells are plated in black-walled 384-well plates (Greiner, 781091) at densities in accordance with their doubling time (for MEFs typically 1,000 cells/well in 20 m ⁇ ), using the Multidrop Combi Reagent Dispenser (Thermo). They are then incubated overnight at 37 °C in a humidified atmosphere of 5% CO2 prior to drug addition.
  • Compound and DMSO addition to microplates is performed using the AccessTM Laboratory Workstation (Labcyte®) and Echo 555 (Labcyte®) liquid handler. Source plates with compounds and DMSO are prepared, and the Echo 555 is used to transfer 50 nL of compound, DMSO, or combination to the appropriate wells.
  • Cells are incubated with compounds for 72h. All conditions are done in triplicate and experiments performed at least thrice. Cellular ATP levels (an indicator of cell count) are determined with the CellTiter-Glo (CTG, Promega G7573) luminescence assay, using an EnVision Plate Reader (PerkinElmer).
  • Plates are harvested at two time points. At the time of drug addition, one plate for each cell line with no compounds added receives 5 pL of media and are harvested to represent a measurement of the cell population at the time of compound addition (TO). After 72 h incubation, the compound-treated plates are harvested using CTG reagent and the luminescence is read using the EnVision giving control growth (C) and compound treated well (T72) measurements. Growth inhibition is calculated by:
  • Cells (MEF K-Ras Q61R, K-Ras G12D, and Myr-K-Ras G12D/C185S) are rinsed thrice with ice-cold PBS and then are lysed on ice with ice-cold TNE buffer supplemented with Halt protease and phosphatase inhibitors (Thermo Scientific). This is then centrifuged at 15,000g for 15 minutes to collect whole-cell lysates. Protein concentration is measured with the BCA protein assay (Pierce). Thirty micrograms of total protein per sample is loaded into 4%-l2% NuPAGE Bis-Tris gradient gels (Life Technologies) and separated by SDS-PAGE. Proteins are transferred to polyvinylidene difluoride (PVDF) membranes. The following antibodies are used for immunoblotting: mouse monoclonal anti-K-Ras (Sigma
  • WH0003845M1 clone 3B10-2F2
  • mouse anti-Ras Thermo 1862335
  • rabbit anti-pERKl/2 T202/Y204; Cell Signaling Technology 4370
  • mouse anti-ERKl/2 Cell Signaling
  • cells (MEF K-Ras G12D, K-Ras G12V, and K- Ras WT) are seeded at 2xl0 5 onto lO-cm Petri dishes and allowed to grow for 24 h.
  • Compounds are added to the medium to a final concentration 10 - 30 mM for 72h.
  • Cells are rinsed three times with ice-cold PBS, then digitonin [300 m ⁇ of 190 mg/ml in lysis buffer (PBS containing 75 mM KC1, 250 mM sucrose and Halt protease and phosphatase inhibitors (Thermo)] is added for 10 min on ice. Cells are then scraped gently and centrifuged 10 min at 12,000 at 4 °C.
  • the supernatant (cytosolic fraction) is removed, and the remaining pellet (membrane fraction) is resuspended in 100 m ⁇ of TNE lysis buffer (25 mM HEPES buffer containing 150 mM NaCl, 5 mM MgCl 2 , 1% SDS, 10% glycerol, 2.5 mM EDTA, supplemented with Halt protease and phosphatase inhibitors) and allowed to incubate for 30 min before processing with standard immunoblot protocol.
  • TNE lysis buffer 25 mM HEPES buffer containing 150 mM NaCl, 5 mM MgCl 2 , 1% SDS, 10% glycerol, 2.5 mM EDTA, supplemented with Halt protease and phosphatase inhibitors
  • mouse monoclonal anti-K-Ras (Sigma WH0003845M1, clone 3B10-2F2)
  • mouse anti- Ras Thermo 1862335
  • mouse anti-MEKl/2 Cell Signaling Technology 4694
  • rabbit anti-Na,K-ATPase Cell Signaling Technology 3010
  • Example III-7 Tumor Xenograft
  • Human pancreas or lung adenocarcinoma cell lines are obtained from the American Type Culture Collection and cultured according to the cell supplier’s protocol, for a maximum of four passages before use. Cells are harvested at 70-80% confluence, washed with phosphate buffered saline, suspended in phosphate buffered saline, and implanted subcutaneously at 5 x 10 s cells/0.2 mL into NCr nu/nu athymic mice, obtained from Charles River. Frederick National Laboratory for Cancer Research is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals.
  • mice are distributed randomly into groups of 12 for treatment.
  • Compounds are injected into the tail veins of the mice, at 100 pmol/kg body weight, 3 times per week for 4 weeks. Control groups are treated with saline. Mice are weighed, and tumors are measured 2 times per week. Tumor volumes in mm 3 are estimated by the formula (p/2 x length c width 2 ). Mice are euthanized almost immediately after the last treatment. Blood is collected under isoflurane anesthesia. Tumors are removed and frozen immediately for biochemical analysis.

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Abstract

L'invention concerne des composés possédant une fraction cyanoacrylamide. L'invention concerne également des compositions pharmaceutiques comprenant de tels composés, et des procédés d'utilisation de ces composés et compositions pharmaceutiques pour inhiber le traitement post-traduction de précurseurs de K-Ras, et pour traiter des troubles chez un sujet en ayant besoin.
PCT/US2019/027876 2018-04-18 2019-04-17 Modulateurs de k-ras possédant une fraction cyanoacrylamide Ceased WO2019204442A1 (fr)

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WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2023205701A1 (fr) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Hétérocycles macrocycliques et leurs utilisations
US12012403B2 (en) 2021-08-18 2024-06-18 Chemocentryx, Inc. Aryl sulfonyl compounds as CCR6 inhibitors
US12018016B2 (en) 2021-08-18 2024-06-25 Amgen Inc. Aryl sulfonyl (hydroxy) piperidines as CCR6 inhibitors
EP4389751A1 (fr) 2021-09-03 2024-06-26 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2024243441A1 (fr) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
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
WO2025171055A1 (fr) 2024-02-06 2025-08-14 Kumquat Biosciences Inc. Conjugués hétérocycliques et leurs utilisations
WO2025230971A1 (fr) 2024-04-30 2025-11-06 Kumquat Biosciences Inc. Hétérocycles macrocycliques en tant qu'agents anticancéreux

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WO2014093230A2 (fr) * 2012-12-10 2014-06-19 Merck Patent Gmbh Compositions et procédés de fabrication de composés pyrimidine et pyridine ayant une activité inhibitrice de btk

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DATABASE PubChem compound 25 January 2012 (2012-01-25), "(Z)-2-Cyano-3-[1-(4-methoxyphenyl)-2,5-dimethylpyrrol-3-yl]-N-[(1-propan-2-ylpyrrolidin-3-yl)methyl]prop-2-enamide", XP055647574, retrieved from NCBI Database accession no. 56314596 *
DATABASE PubChem compound 25 January 2012 (2012-01-25), "(Z)-2-Cyano-N-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]methyl]-3-[1-(1-methoxypropan-2-yl)-2,5-dimethylpyrrol-3-yl]prop-2-enamide", XP055647570, retrieved from NCBI Database accession no. 56178526 *
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
US12012403B2 (en) 2021-08-18 2024-06-18 Chemocentryx, Inc. Aryl sulfonyl compounds as CCR6 inhibitors
US12018016B2 (en) 2021-08-18 2024-06-25 Amgen Inc. Aryl sulfonyl (hydroxy) piperidines as CCR6 inhibitors
EP4389751A1 (fr) 2021-09-03 2024-06-26 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2023205701A1 (fr) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Hétérocycles macrocycliques et leurs utilisations
WO2024243441A1 (fr) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
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
WO2025171055A1 (fr) 2024-02-06 2025-08-14 Kumquat Biosciences Inc. Conjugués hétérocycliques et leurs utilisations
WO2025230971A1 (fr) 2024-04-30 2025-11-06 Kumquat Biosciences Inc. Hétérocycles macrocycliques en tant qu'agents anticancéreux

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