WO2019204505A2 - Modulateurs de k-ras avec une fraction de sulfonamide de vinyle - Google Patents

Modulateurs de k-ras avec une fraction de sulfonamide de vinyle Download PDF

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WO2019204505A2
WO2019204505A2 PCT/US2019/027959 US2019027959W WO2019204505A2 WO 2019204505 A2 WO2019204505 A2 WO 2019204505A2 US 2019027959 W US2019027959 W US 2019027959W WO 2019204505 A2 WO2019204505 A2 WO 2019204505A2
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alkyl
heterocycloalkyl
formula
cycloalkyl
substituted
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PCT/US2019/027959
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WO2019204505A3 (fr
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Anjali Pandey
Swapan Kumar Samanta
Athisayamani Jeyaraj DURAISWAMY
Anna E. Maciag
David Turner
Matthew Alexander James Duncton
Vandana KUMARI
Adam R. Renslo
Eddy Low
Christopher BRASSARD
Holly V. ADCOCK
Daniel HAMZA
Stuart T. ONIONS
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Theras, Inc.
Leidos Biomedical Research, Inc.
The Regents Of The University Of California
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Publication of WO2019204505A2 publication Critical patent/WO2019204505A2/fr
Publication of WO2019204505A3 publication Critical patent/WO2019204505A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present disclosure relates generally to compounds that inhibit K-Ras, or the post-translational processing of Ras that produces a mature, fully-processed K-Ras protein, and more specifically to inhibitors with a vinyl sulfonamide moiety.
  • KRAS is one of the most frequently mutated oncogenes implicated in human cancer.
  • the KRAS oncogene encodes the K-Ras protein, which is part of 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.
  • KRAS Activating mutations in KRAS are common in many different human cancers. Thus, what is needed are effective inhibitors of K-Ras, and effective inhibitors of the post translational processing of Ras that produces a mature, fully-processed K-Ras protein.
  • R xl , R x2 , and R x3 are independently hydrogen, -CN, or alkyl; or R x2 and R x3 together form alkenyl; or R xl and R x2 together with the carbon atoms to which they are attached form heterocycloalkenyl or cycloalkenyl; or R al and R x2 together with the atoms to which they are attached form heterocycloalkenyl; wherein each alkyl, alkenyl, heteroaryl, heterocycloalkenyl, and cycloalkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and -OR x4 , wherein each R x4 is independently H, alkyl, or haloalkyl;
  • A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2 -, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2 -, -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2 -; each R a6 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2 -, -S(0)NR a46 -, -C(S)-, or -C(O)-; R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -SCkR 310 , wherein when A is phenyl, R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, cycloalkyl,
  • heterocycloalkyl -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -S0 2 R al °; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently
  • each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
  • each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl
  • cycloalkyl halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl
  • 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
  • R a2 and R a3 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 a5 is independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a50 , R a51 , R a52 , R a53 , R a54 , R a55 , R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R al1 , R al2 , R al3 , R al6 , R al7 , R al8 , R al9 , R a20 , R 321 , R a35 , R a54 , and R a55 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R a58 is independently unsubstituted or substituted with one or more substituents independently selected from
  • each R a22 , R a23 , R a24 , R a36 , R a37 , R a38 , and R a39 is independently hydrogen, alkyl, or haloalkyl; wherein each alkyl or haloalkyl or R a22 and R a23 is independently
  • each R a40 is independently hydrogen, alkyl, haloalkyl, aryl, or heteroaryl, wherein each aryl or heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
  • each R a40 is independently hydrogen, alkyl, haloalkyl, aryl, or heteroaryl, wherein each aryl or heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
  • the compound of Formula (X) is a compound of Formula (X-I):
  • A is 4- to lO-membered heterocycloalkyl
  • B, X, R xl , R x2 , R x3 , R al , R a2 , R a3 , R a4 , R a5 , m, and n are as defined for Formula (X).
  • the compound of Formula (X) is a compound of Formula (X-A):
  • the compound of Formula (X) is a compound of Formula (X-C):
  • the compound of Formula (X) is a compound of Formula (X-B):
  • Y is -C(R a45 )2-— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0) 2- -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ‘)2— , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • R xl , R x2 , R x3 , R al , R a2 , R a3 , R a4 , R a5 , R a6 , R a46 , and n are as defined for Formula (X).
  • the compound of Formula (X) is a compound of Formula (X-A- i):
  • the compound of Formula (X) is a compound of Formula (X-C- i):
  • R xl , R x2 , R x3 , R al , R a2 , R a3 , R a4 , and R a5 are as defined in Formula (X).
  • the compound of Formula (X) is a compound of Formula (I):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2 -, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2 -, -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2 -; each R a6 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -S02R al °, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R a3 and one R a4 , 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; or R al and R a2 , together with the atoms to which they are attached, form a
  • each R a5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a22 , R a23 , R a24 , R a36 , R a37 , R a38 , R a39 , and R a40 is independently hydrogen, alkyl, or haloalkyl;
  • m is an integer from 0 to 13; and
  • n is an integer from 0 to 1 1.
  • A is 5- or 6-membered heterocycloalkyl.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (I- A):
  • the compound of Formula (X) or Formula (I) is a compound of Formula (I-B):
  • Y is -C(R a45 )2-— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0) 2- -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ; r is 0, 1, or 2; p is an integer from 0 to 7; and B, R al , R a2 , R a3 , R a4 , R a5 , R a6 , R a46 , and n are as defined for Formula (I).
  • Y is -CFh-
  • B is heteroaryl, cycloalkyl, or heterocycloalkyl.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (I-A-i):
  • R a , R a2 , R a3 , R a4 , and R a5 are as defined for Formula (I).
  • R a5 is: wherein:
  • R a25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R a26 and R a27 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 a32 , and - NR a33 R a34 ;
  • each R a2X , R a29 , R a30 , R a31 , R a32 , R a33 , R a34 , R a41 , R a42 , R a43 , and R a44 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
  • X is — S(0)2— .
  • X is -C(O)-.
  • X is -CFh-
  • a pharmaceutical composition comprising a compound of Formula (X) (such as Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (X-I), Formula (X-A), Formula (X-A- i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I-A), Formula (I-A-i), or Formula (I-B), or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of a K-Ras protein in a subject in need thereof by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (X) (such as Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X- C), Formula (X-C-i), Formula (I-B), Formula (I-A), Formula (I-A-i), or Formula (I-B), or a pharmaceutically acceptable salt thereof.
  • 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 (X) (such as Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (X- I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I-B), Formula (I- A), Formula (I-A-i), or Formula (I-B), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (X) (such as Formula (I)), or a 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.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I-B), Formula (I- A), Formula (I-A-i), or Formula (I-B), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (X) (such as Formula (I)), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I-B), Formula (I- A), Formula (I-A-i), or Formula (I-B), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (X) (such as Formula (I)), or a 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 (X) or Formula (I) is a compound of Formula (X-I), Formula (X-A), Formula (X-A- i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I-B), Formula (I-A), Formula (I-A-i), or Formula (I-B), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (X) (such as Formula (I)), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
  • the compound of Formula (X) or Formula (I) is a compound of Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X- B), Formula (X-C), Formula (X-C-i), Formula (I-B), Formula (I-A), Formula (I-A-i), or Formula (I-B), or a pharmaceutically acceptable salt thereof.
  • 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.
  • FIG. 1 depicts an immunoblot demonstrating the effect of compound 1-0175 on the level of K-Ras in mouse embryonic fibroblast (MEF) cell lines expressing KRAS Q61R, KRAS G12D, or Myr-KRAS G12D/C185S genes.
  • Cells were treated with compound (1-0175), or corresponding volume of DMSO (D), or left untreated (0). Seventy -two hours after treatment was initiated, cells were lysed, then 30 micrograms of total protein lysate was resolved by SDS-PAGE, followed by immunoblotting with antibodies as described in the Experimental section.
  • FIG. 2 depicts an immunoblot demonstrating the effect of compound 1-0175 on K- Ras membrane localization in the different MEF cell lines K-Ras4b G12D, K-Ras4b G12V, and H-Ras wild type (WT).
  • WT H-Ras wild type
  • “WCL” refers to whole cell lysate. Cells were treated with I- 0175 at 12.5 or 25 mM, or DMSO volume corresponding to the highest compound dose (D). Seventy-two hours after treatment was initiated, cells were fractionated using digitonin in a sucrose buffer (following the protocol provided in Experimental section). Corresponding cytosolic and membrane lysates (30 pg protein) were resolved by SDS-PAGE, followed by immunoblot. Anti-MEK antibodies were used as a cytosolic fraction loading control, and anti-Na/K ATPase antibodies as a control for a membrane fraction.
  • FIG. 3 depicts confocal images of the effect of compound 1-0175 on cell membrane localization of K-Ras4b in HeLa cells.
  • FIG. 4 depicts confocal images of the effect of compound 1-0176 on HeLa cells expressing eGFP-KRAS4b G12D in a doxycycline-inducible system.
  • KRAS gene expression was induced with doxy cy cline, followed immediately with addition of compound 1-0176 at the concentrations depicted on the panels.
  • the presence of compound 1-0176 decreased K- Ras membrane localization.
  • FIGS. 5A-5D depicts results from cell proliferation assays with selected compounds in MEF cells after 72 h incubation, (ICso values, mM).
  • FIG. 6 is a table listing the ICso ratio of selected compounds in G12D vs. Myr- G12D MEFs.
  • FIG. 7 is a graph comparing the level of covalent modification to Cl 85 (measured by MALDI-TOF MS) with calculated ICso ratios (of K-Ras4b G12D to Myr-K-Ras
  • FIGS. 8A-8C are heat maps representing ICso values for selected compounds in mouse embryonic fibroblast (MEF) cells. Numbers represent ICso values, with lowest ICso (black) indicating highest sensitivity.
  • bracketed compounds demonstrated desirable selectivity for MEF cells expressing oncogenic mutant of KRAS4b (such as G12V, G12D or Q61R), compared to MEFs expressing HRAS, or control cell line expressing Myr- KRASG12D/C185S.
  • bracketed compounds demonstrated higher activity in MEFs expressing KRAS4b G12V , compared to KRAS4a, HRAS, or Myr-KRAS G12D/C185S cells.
  • FIG. 9 is a heat map representing ICso values for selected compounds in MEF cells expressing the proteins K-Ras4b G12D, K-Ras4b G12V, Myr-K-Ras G12D/C185S, or Myr- K-Ras G12V/C185S.
  • FIG. 10 is a table summarizing the data displayed in FIG. 9.
  • a compound such as a compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), or Formula (I-B-i), or a pharmaceutically acceptable salt of any of the foregoing, as described below.
  • this compound may inhibit K-Ras, or may inhibit the post-translational processing of K-Ras that produces a mature, fully-processed 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 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 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 in K-Ras.
  • the compound inhibits K-Ras, or decreases the level of K-Ras, or inhibits the post-translational processing of K-Ras to produce a K-Ras protein, such as K-Ras4b.
  • R xl , R x2 , and R x3 are independently hydrogen, -CN, or alkyl; or R x2 and R x3 together form alkenyl; or R xl and R x2 together with the carbon atoms to which they are attached form heterocycloalkenyl or cycloalkenyl; or R al and R x2 together with the atoms to which they are attached form heterocycloalkenyl; wherein each alkyl, alkylene, heteroaryl, heterocycloalkenyl, and cycloalkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and -OR x4 , wherein each R x4 is independently H, alkyl, or haloalkyl;
  • A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ; each R a6 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N0 2 , -CN, -S0 2 NH 2 , -NR a7 R a8 , -OR a9 , and -S0 2 R al °, wherein when A is phenyl, R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, cycloalkyl,
  • heterocycloalkyl -N0 2 , -CN, -S0 2 NH 2 , -NR a7 R a8 , -OR a9 , and -S0 2 R al °; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently
  • each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N0 2 , -CN, -S0 2 NH 2 , -NR a7 R a8 , -OR a9 , 0, -SR a47 , and -S0 2 R al °, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R a3 and one R a4 , 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; or R al and R a2 , together with the atoms to which they are attached, form a
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or R a2 and R a3 , 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; or, when X is -S(O)-, -S(0)2-, -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; or, when X is -C(O)-, R al and one R a4 , together with the atoms to which they are attached, form a spirocycle with ring A, wherein the spirocycle is
  • each R a5 is independently selected from the group consisting of halo, alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each alkenyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a50 , R a51 , R a52 , R a53 , R a54 , R a55 , R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
  • each R a40 is independently hydrogen, alkyl, haloalkyl, aryl, or heteroaryl, wherein each aryl or heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
  • m is an integer from 0 to 13; and n is an integer from 0 to 11.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain.
  • alkyl as used herein has 1 to 50 carbon atoms ((Ci-Cso)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-Ce)alkyl), or 1 to 4 carbon atoms ((Ci-C 4 )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 CHFCH2CH 2 Br.
  • 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 ((C2-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- C 4 )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.
  • Cycloalkenyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon comprising one or more carbon-carbon double bonds.
  • cycloalkenyl has 3 to 50 carbon atoms ((C3-Cso)cycloalkenyl), 3 to 20 carbon atoms ((C 3 - C2o)cycloalkenyl), 3 to 12 carbon atoms ((C3-Ci2)cycloalkenyl), 3 to 8 carbon atoms ((C3- C8)cycloalkenyl), 3 to 6 carbon atoms ((C 3 -C 6 )cycloalkenyl), or 3 to 5 carbon atoms ((C3- C 4 )cydoalkenyl).
  • 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-Cso)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- C 4 )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- C 5 o)cycloalkyl), 3 to 20 carbon atoms ((C 3 -C2o)cycloalkyl), 3 to 12 carbon atoms ((C3- Ci2)cycloalkyl), 3 to 8 carbon atoms ((C 3 -C8)cycloalkyl), 3 to 6 carbon atoms ((C3- C 6 )cycloalkyl), or 3 to 5 carbon atoms ((C 3 -C 4 )cycloalkyl).
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro- liT-indene, decahydronaphthalene, cubane, bicyclo[3.l.0]hexane, and bicyclo[ 1.1.1 ]pentane.
  • 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; l,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 of N, O, and S ( e.g ., chromane; thiochromane; 2,3-dihydrobenzofuran; indoline).
  • aryl as used herein has from 6 to 14 carbon atoms ((C 6 - Ci 4 )aryl), or 6 to 10 carbon atoms ((C 6 -Cio)aryl).
  • aryl may connect to one or more substituents or moieties of the formulae described herein through any atom for which valency permits.
  • aryl comprises one ring, two fused rings, three fused rings, four fused rings, or more.
  • Heteroaryl 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, lO-membered, l l-membered, or l2-membered heteroaryl).
  • the heteroaryl comprises greater than 12 ring atoms, for example 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, or greater. In certain embodiments, the heteroaryl comprises between 5 to 16 ring atoms, between 5 to 14 ring atoms, between 5 to 12 ring atoms, between 5 to 10 ring atoms, or between 5 to 8 ring atoms. In some embodiments, 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).
  • heteroaryl includes polycyclic groups with two fused aromatic rings, wherein each ring comprises at least one ring heteroatom (e.g, naphthyridinyl).
  • each ring comprises at least one ring heteroatom (e.g, naphthyridinyl).
  • heteroaryl comprises one ring, two rings, three rings, four rings, five rings, between one to four rings, or between one to three rings.
  • 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.
  • heteroaryl comprises greater than 5 ring heteroatoms.
  • a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • 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).
  • the heterocycloalkyl group comprises more than 12 ring atoms, for example 13 ring atoms, 14 ring atoms, 15 ring atoms, or 16 ring atoms, or more. In certain embodiments, the heterocycloalkyl comprises between 5 to 16 ring atoms, between 5 to 14 ring atoms, between 5 to 12 ring atoms, between 5 to 10 ring atoms, or between 5 to 8 ring atoms.
  • 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 with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • the heterocycloalkyl comprises one ring, two rings, three rings, four rings, or more, for example as a polycyclic fused system.
  • heterocycloalkyl comprising multiple rings includes spirocyclic systems in which one or more rings comprise one or more heteratoms.
  • heterocycloalkyl 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.“Heterocycloalkenyl”, as used herein, is a heterocycloalkyl comprising one or more ring double bonds.
  • Heterocycloalkenyl may include, for example, l,2-dihydropyridine, 2,5-dihydrofuran, and 2, 5 -dihydro- 1/7- pyrrole.
  • 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, and 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-C 6 )alkyl” (which may also be referred to as C1-C6 alkyl, Ci- 6 alkyl, or Cl -6 alkyl) is intended to encompass Cl, C 2, C3, C 4 , Cs, Ce, Ci-6, Ci-s, CM, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C 4 - 6 , C4-5, and C5-6 alkyl.
  • A is heteroaryl, cycloalkyl, or heterocycloalkyl.
  • A is 5- to lO-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.
  • A 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.
  • A is
  • A is heterocycloalkyl.
  • A is 3- to
  • A is 5- to 10- membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, A is 5- or 6-membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, A is 9- or lO-membered
  • heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • A is a 5,5-ring fused
  • A is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or tropanyl.
  • A is heteroaryl.
  • A is 5- to 10- membered heteroaryl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • A is 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • A is 9- or lO-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • A 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. In some embodiments, A is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl.
  • A 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.
  • A is aryl.
  • A is (C6-Cio)aryl, such as C6-aryl, (C7-Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl.
  • A is phenyl or naphthyl.
  • A 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.
  • A is cycloalkyl.
  • A is (C 3 - Cio)cycloalkyl.
  • A is (C 5 -Cio)cycloalkyl.
  • A is (C 5 -C7)cycloalkyl.
  • A is (C8-Cio)cycloalkyl.
  • A is C3-cycloalkyl, C 4 -cycloalkyl, Cs-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or Cio-cycloalkyl.
  • A is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl.
  • A is
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tri cyclooctyl.
  • the compound of Formula (X) is a compound of Formula (X-
  • A is 4- to lO-membered heterocycloalkyl
  • B, X, R xl , R x2 , R x3 , R al , R a2 , R a3 , R a4 , R a5 , m, and n are as defined for
  • the compound of Formula (X) or Formula (X-I) is a compound of Formula (X-A):
  • the compound of Formula (X) or Formula (X-I) is a compound of Formula (X-C):
  • the compound of Formula (X) or Formula (X-I) is a compound of Formula (X-B):
  • Y is -C(R a45 )2-— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0) 2- -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ‘)2— , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • r 0, 1, or 2;
  • p is an integer from 0 to 7; are as defined for Formula
  • the compound of Formula (X) is a compound of Formula (X- A-i):
  • R xl , R x2 , R x3 , R al , R a2 , R a3 , R a4 , and R a5 are as defined in Formula (X).
  • the compound of Formula (X) is a compound of Formula (X- C-i):
  • p is an integer from 0 to 6. In other embodiments,
  • R xl , R 52 , and R x3 are unsubstituted or substituted alkyl.
  • two of R xl , R x2 , and R x3 is unsubstituted or substituted alkyl.
  • three of R xl , R x2 , and R x3 is unsubstituted or substituted alkyl.
  • the alkyl is (Ci-C 4 )alkyl. In certain embodiments, the alkyl is unsubstituted. In other embodiments, the alkyl is substituted with one or more substituents independently selected from the group consisting of halo, -OH, -O-alkyl, and -O- haloalkyl. In certain embodiments, the alkyl is substituted with one to four substituents independently selected from the group consisting of halo, -OH, -0-(Ci-C 4 )alkyl, and -0-(Ci- C 4 )haloalkyl.
  • one of R xl , R x2 , and R x3 is -CN.
  • R x2 and R x3 together form alkenyl.
  • R 52 and R x3 together with the carbon to which they are attached form a (C2-Cio)alkenyl.
  • R 52 and R x3 together with the carbon to which they are attached form a C2-alkenyl.
  • the alkenyl is substituted with one or more substituents independently selected from the group consisting of halo and -OR x4 , wherein each R x4 is independently H, alkyl, or haloalkyl.
  • the alkenyl is substituted with one or more substituents independently selected from the group consisting of halo, -OH, -0(Ci-C 6 )alkyl, and -0(Ci-C 6 )haloalkyl.
  • each halo is independently chloro or fluoro.
  • the alkenyl is unsubstituted.
  • R xl is hydrogen.
  • R xl and R x2 together with the carbon atoms to which they are attached form heterocycloalkenyl, or cycloalkenyl.
  • the heterocycloalkenyl is a 5- to lO-membered heterocycloalkenyl, or a 5- to 8-membered heterocycloalkenyl.
  • the cycloalkenyl is a (C 4 -Cio)cycloalkenyl, or a (C 5 -C8)cycloalkenyl, or a (C 5 -C6)cycloalkenyl.
  • the heterocycloalkenyl is a 5- to lO-membered heterocycloalkenyl, or a 5- to 8-membered heterocycloalkenyl.
  • the cycloalkenyl is a (C 4 -Cio)cycloalkenyl, or a (C 5 -C8)cycloalkenyl, or
  • heterocycloalkenyl or cycloalkenyl is unsubstituted.
  • the heterocycloalkenyl or cycloalkenyl is unsubstituted.
  • heterocycloalkenyl or cycloalkenyl is substituted with one or more substituents independently selected from the group consisting of halo and -OR x4 , wherein each R x4 is independently H, alkyl, or haloalkyl.
  • the heterocycloalkenyl or cycloalkenyl is substituted with one or more substituents independently selected from the group consisting of halo, -OH, -0(Ci-C6)alkyl, and -0(Ci-C6)haloalkyl.
  • each halo is independently chloro or fluoro.
  • R al and R x2 together with the atoms to which they are attached form heterocycloalkenyl.
  • the heterocycloalkenyl is a 5- to lO-membered heterocycloalkenyl, or a 5- to 8-membered heterocycloalkenyl, or a 5- membered heterocycloalkenyl, or a 6-membered heterocycloalkenyl.
  • the heterocycloalkenyl comprises one double bond.
  • the heterocycloalkenyl comprises one double bond.
  • heterocycloalkyl is substituted with one or more substituents independently selected from the group consisting of halo and -OR x4 , wherein each R x4 is independently H, alkyl, or haloalkyl.
  • the heterocycloalkenyl is substituted with one or more substituents independently selected from the group consisting of halo, -OH, -0(Ci- C6)alkyl, and -0(Ci-C6)haloalkyl.
  • each halo is independently chloro or fluoro.
  • the heterocycloalkenyl is unsubstituted.
  • R al and R x2 together with the atoms to which they are attached form an
  • R xl is hydrogen. In some embodiments, R xl is hydrogen.
  • R x2 is hydrogen. In other embodiments, R x3 is hydrogen. In certain embodiments, both R x2 and R x3 are hydrogen. In still further embodiments, R xl and R x2 are hydrogen. In other embodiments, both R xl and R x3 are hydrogen. In certain embodiments, each of R xl , R x2 , and R x3 are hydrogen.
  • the compound of Formula (X) is a compound of Formula (I):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ; each R a6 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -SCkR 310 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , 0, -SR a47 , and -S0 2 R al °, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R a3 and one R a4 , 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; or R al and R a2 , together with the atoms to which they are attached, form a
  • R a2 and R a3 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; or, when X is -S(O)-, -S(0)2-, -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each R a5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a50 , R a51 , R a52 , R a53 , R a54 , R a55 , R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R al1 , R al2 , R al3 , R al6 , R al7 , R al8 , R al9 , R a20 , R 321 , and R a35 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R a58 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycl
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR a22 R a2 ⁇ -OR a24 , and
  • each R a22 , R a23 , R a24 , R a36 , R a37 , R a38 , R a39 , and R a40 is independently hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11.
  • each R a4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN,
  • heterocycloalkyl such as 3- to 8-membered heterocycloalkyl, 3- to 6-membered
  • heterocycloalkyl or 5- to 6-membered heterocycloalkyl
  • aryl such as (C 6 -Cio)aryl
  • (Cio)aryl or phenyl
  • heteroaryl such as 5- to lO-membered heteroaryl, 5- to 9- membered heteroaryl, or 5- to 6-membered heteroaryl.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • each R a6 is independently hydrogen, halo, alkyl, or haloalkyl
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -SCkR 310 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R a3 and one R a4 , 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; or R al and R a2 , together with the atoms to which they are attached, form a
  • R a2 and R a3 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; or, when X is -S(O)-, -S(0)2-, -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each R a5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a50 , R a51 , R a52 , R a53 , R a54 , R a55 , R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
  • heterocycloalkyl aryl, heteroaryl, alkynyl, or haloalkynyl
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R al1 , R al2 , R al3 , R al6 , R al7 , R al8 , R al9 , R a20 , R 321 , and R a35 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R a58 is
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR a22 R a23 , -OR a24 , and -SFs;
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ; each R a6 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R al is hydrogen, alkyl, or cycloalkyl, wherein when R al is alkyl, X is -S(O)-, -S(0)2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -SCkR 310 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , 0, -SR a47 , and -S02R al °, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl, or halocycloalkyl or two to four R a4 , together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or R a2 and one R a4 , together with the atoms to which they are attached, form a
  • heterocycloalkyl or R a2 and R a3 , together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl; or, when X is -S(O)-, -S(0)2-, -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl; each R a5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each R al1 , R al2 , R al9 , R a20 , and R a21 is independently hydrogen, alkyl,
  • A is a 4-, 5-, 6-, or 7-membered heterocycloalkyl. In some embodiments, 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.
  • 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.
  • A is pyrrolidinyl.
  • A is a 4-membered heterocycloalkyl.
  • the compound of Formula (I) is a compound of Formula (I-
  • the compound of Formula (I) is a compound of Formula (I- C):
  • 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 (I) is a compound of Formula (I-
  • Y is -C(R a45 )2-— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0) 2- -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • r 0, 1, or 2;
  • p is an integer from 0 to 7;
  • R al , R a2 , R a3 , R a4 , R a5 , R a6 , R a46 , and n are as defined for Formula (I).
  • Y is -C(R a45 )2-, wherein each R a45 is independently hydrogen or R a4 .
  • Y is -CFh-
  • Y is -CHR a4 -.
  • Y is -C(R a4 )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 a45 )-, wherein each R a45 is independently hydrogen or R a4 . For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NR a4 -.
  • 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.
  • B is heteroaryl, cycloalkyl, or heterocycloalkyl.
  • B is 5- to lO-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.
  • 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 lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms
  • 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 lO-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. In some embodiments, B is 9- or lO-membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, B is a 5,5-ring fused heterocycloalkyl, 6,6-ring fused heterocycloalkyl, or 5,6- ring fused heterocycloalkyl.
  • B is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or tropanyl.
  • B is:
  • B is heteroaryl.
  • B is 5- to lO-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
  • 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 naphthyl.
  • 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.
  • B is (Cs- Cio)cycloalkyl.
  • B is (C 5 -C7)cycloalkyl.
  • B is (C8-Cio)cycloalkyl.
  • B is C3-cycloalkyl, C 4 -cycloalkyl, Cs- cycloalkyl, C 6 -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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tri cyclooctyl.
  • B is:
  • B may be unsubstituted or substituted with one to eleven R a5 as described in Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), and Formula (I-C), as valency allows.
  • B is ⁇ ( B )— (R a5 ) n (R a5 )n-T
  • 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 10.
  • R a5 When multiple instances of a substituent (for example, R a ) are present, it should be understood that they may be optionally different unless otherwise indicated.
  • 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. In some embodiments, n is 2. In still other embodiments, n is 3. In still further embodiments, n is 4.
  • B is phenyl
  • n is an integer from 0 to 5.
  • B is phenyl
  • n is an integer from 0 to 5.
  • R a5 When multiple instances of a substituent (for example, R a5 ) are present, it should be understood that they may be optionally different unless otherwise indicated.
  • the compound of Formula (I) is a compound of Formula (I-A- i):
  • the compound of Formula (I) is a compound of Formula (I-
  • R al , R a2 , R a3 , R a4 , and R a5 are as defined for Formula (I).
  • 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 (I) is a compound of Formula (I-B-i):
  • Y is -C(R a45 )2-,— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2 -, wherein when Y is -CH2-, X is -S(O)-, -S(0) 2 - -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2 -; r is 0, 1, or 2; p is an integer from 0 to 7; and R al , R a2 , R a3 , R a4 , R a5 , R a6 , R a46 , and n are as defined for Formula (I).
  • Y is -C(R a45 )2-, wherein each R a45 is independently hydrogen or R a4 .
  • Y is -CFh-
  • Y is -CHR a4 -.
  • Y is -C(R a4 )2-
  • Y is -S(0)r-, wherein 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 a45 )-, wherein each R a45 is independently hydrogen or R a4 . For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NR a4 -.
  • 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.
  • p is an integer from 0 to 6. In other embodiments,
  • p is an integer from 0 to 6.
  • each R a5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, - NO2, -CN,
  • one or more R a5 is independently selected from the group consisting of halo; -0-(Ci-C4)alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl;
  • one or more R a5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl.
  • each R a5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, and -CN.
  • one or more R a5 is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2,
  • At least one R a5 is halo, -0-(Ci-C6)alkyl,
  • At least one R a5 is chloro, fluoro, -OCH 3 , -OCH2CH 3 , -OCH(CH 3 )2, -CH2F, -CHF2, -CFs, -OCH2F, -OCHF2, -OCFs, or -CN.
  • at least one R a5 is chloro, fluoro, -OCH3, or -CN.
  • each R a5 is independently chloro, fluoro, -OCH3, or -CN.
  • At least one R a5 is alkyl, wherein each alky is independently unsubstituted or substituted with one or more substituents
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R a58 is independently (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8- membered heteroaryl.
  • the alkyl is unbranched.
  • the alkyl is branched.
  • at least one R a5 is alkyl, wherein the alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halocycloalkyl,
  • the alkyl is (Ci-Ci2)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In some embodiments, the alkyl is unbranched. In other embodiments, the alkyl is branched.
  • the alkyl is (Ci-C8)alkyl, wherein the alkyl is unsubstituted or substituted as described herein. In further embodiments, the alkyl is (Ci-Ce)alkyl, wherein the alkyl is unsubstituted or substituted as described herein. In still other embodiments, the alkyl is (Ci-C 4 )alkyl, wherein the alkyl is unsubstituted or substituted as described herein. In some embodiments, at least one R a5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, difluoromethyl, or fluoromethyl.
  • each R a35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl.
  • R a35 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
  • At least one R a5 is branched alkyl.
  • the branched alkyl is (C3-C5) branched alkyl.
  • the branched alkyl is isopropyl.
  • each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R a58 is independently unsubstituted or substituted with one or more substituents
  • each R a20 and R a21 are independently selected from the group consisting of hydrogen; unsubstituted or substituted cycloalkyl; unsubstituted or substituted
  • heterocycloalkyl and alkyl, wherein the alkyl is unsubstituted or substituted.
  • R 320 and R 321 are independently alkyl
  • heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -NR a36 R a37 , and -OR 340 .
  • at least one of R 320 and R 321 is not hydrogen. In certain embodiments, both R 320 and R 321 are not hydrogen.
  • At least one R 35 is isopropyl, wherein one terminal methyl of the isopropyl is substituted with phenyl.
  • the phenyl is unsubstituted.
  • the phenyl is substituted with one to three substituents independently selected from the group consisting of halo, haloalkyl, -NR a22 R a23 , and -OR a24 .
  • R a22 , R a23 , and R a24 are independently hydrogen, (Ci-C 4 )alkyl, or (Ci- C 4 )haloalkyl.
  • R a58 is heterocycloalkyl.
  • the heterocycloalkyl is unsubstituted. In other embodiments, the heterocycloalkyl is substituted.
  • At least one R a5 is -NR all R a12 .
  • at least one of R al1 and R al2 is not hydrogen.
  • both of R al1 and R al2 are not hydrogen.
  • at least one of R al1 and R al2 is substituted alkyl.
  • R al1 and R al2 are substituted alkyl.
  • R al1 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted.
  • the aryl or heteroaryl is unsubstituted.
  • the aryl or heteroaryl is substituted with one or more substituents selected from the group consisting of halo, haloalkyl, -SFs, -NR a36 R a37 , and - OR a40 .
  • heterocycloalkyl wherein the heterocycloalkyl is independently unsubstituted or substituted. In some embodiments, the heterocycloalkyl is unsubstituted. In other embodiments, the heterocycloalkyl is substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, -SFs, -NR a36 R a37 , and -OR a40 . In some embodiments, when R al1 or R al2 is alkyl, or both R al1 and R al2 are alkyl, each alkyl is independently (Ci- C 4 )alkyl.
  • R a5 is -NR all R a12 , wherein R al1 is Ci-alkyl substituted with aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and R al2 is hydrogen or alkyl.
  • R al2 is alkyl
  • each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (e.g., substituting the Ci-alkyl of R al1 or alkyl of R al2 ) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -SFs, -NR a36 R a37 , and -OR a40 .
  • each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, and haloalkyl.
  • R a5 is a substituted alkyl of formula (a):
  • R a20 and R a21 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
  • halo 0, -NR a22 R a23 , -OR a24 , alkyl, aryl, and heteroaryl; wherein each alkyl is independently unsubstituted or substituted with one or more halo; and each aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, and haloalkyl.
  • each R a35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl.
  • at least one R a5 is unsubstituted alkenyl.
  • the alkenyl is (C2-Cio)alkenyl. In other embodiments, the alkenyl is (C2-C8)alkenyl. In still further embodiments, the alkenyl is (C2-C6)alkenyl. In yet other embodiments, the alkenyl is (C2-C4)alkenyl. In some embodiments, the alkenyl is branched. In other embodiments, the alkenyl is unbranched.
  • the alkenyl comprises between one to three carbon- carbon double bonds. In other embodiments, the alkenyl comprises one carbon-carbon double bond. In some embodiments, the alkenyl comprises two carbon-carbon double bonds. In still further embodiments, the alkenyl comprises three carbon-carbon double bonds.
  • each R a35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl.
  • at least one R a5 is unsubstituted cycloalkyl.
  • At least one R a5 is aryl, wherein each aryl is independently unsubstituted or substituted with one or more substituents
  • each R a35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R a35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl.
  • R a35 is unsubstituted (Ci-C6)alkyl.
  • R a35 is (Ci-Ce)alkyl substituted with one or more substituents
  • halo 0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NR a22 R a23 , -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci- C6)haloalkyl.
  • at least one R a5 is unsubstituted aryl.
  • heterocycloalkyl (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R a35 is unsubstituted (Ci-C6)alkyl.
  • at least one R a5 is unsubstituted heteroaryl.
  • each R a35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R a35 is unsubstituted (Ci-C6)alkyl.
  • at least one R a5 is unsubstituted heterocycloalkyl.
  • each R al1 , R al2 , R al3 , R al4 , R al5 independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl.
  • each R al1 , R al2 , R al3 , R al4 , R al5 independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl.
  • each R al1 , R al2 , R al3 , R al4 , R al5 independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloal
  • R a57 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C 3 - C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, (C6-Cio)aryl, 3- to lO-membered heteroaryl, (C 2 -C6)alkynyl, or (C 2 -C6)haloalkynyl.
  • each R al4 , R al5 , R al6 , R al7 , R al8 , R a48 , R a49 , R a50 , R a51 , R a52 , R a53 , R a54 , R a55 , R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl.
  • each R al4 , R al5 , R al6 , R al7 , R ai8 , R a48 , R a49 , R a50 , R a51 , R a52 , R a53 , R a54 , R a55 , R a56 , and R a57 is independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, and (C 3 - C6)halocycloalkyl.
  • each R al 1 , R al2 , R al9 , R 320 , and R a21 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl.
  • each R al 1 , R al2 , R al9 , R a20 , and R 321 is independently hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to lO-membered heterocycloalkyl, 3- to lO-membered heteroaryl, or (C6-Cio)aryl.
  • each R al3 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl. In certain embodiments, each R al3 is independently hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to lO-membered
  • heterocycloalkyl (C6-Cio)aryl, 3- to lO-membered heteroaryl, or (C3-C6)alkynyl.
  • heterocycloalkyl, aryl, and heteroaryl of R al 1 , R al2 , R al3 , R al6 , R al7 , R al8 , R al9 , R a20 , R a21 , and R a35 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R a58 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 -NR a22 R a23 , -OR 324 , and -SFs; wherein 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 independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo,
  • each R 322 , R a23 , R 324 , R a36 , R a37 , R a38 , R a39 , and R a40 is independently hydrogen, alkyl, or haloalkyl.
  • each R a22 , R a23 , R a24 , R a36 , R a37 , R a38 , R a39 , and R a40 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C 6 )haloalkyl.
  • R a25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R a2X , R a29 , R a30 , R a31 , R a32 , R a33 , R a34 , R a41 , R a42 , R a43 , and R a44 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl.
  • each R a28 , R a29 , R a30 , R a31 , R a32 , R a33 , R a34 , R a41 , R a42 , R a43 , and R a44 is independently hydrogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, or halobutyl.
  • R a25 is alkyl, wherein the alkyl is unsubstituted or substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is independently
  • substituents independently selected from the group consisting of halo, -SFs, (C3-C6)cycloalkyl, (C3-
  • R a25 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 a25 is unsubstituted (Ci-C6)alkyl. In other embodiments, R a25 is (Ci-Ce)alkyl substituted with 3- to 6-membered heteroaryl. In other embodiments, R a25 is (Ci-Ce)alkyl substituted with phenyl, wherein the phenyl is unsubstituted or substituted with one more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C2-C 6 )alkynyl, (Ci-C 6 )haloalkyl, -OH, -0(Ci-C 6 )alkyl, -SFs, -NHC(0)H, and -NHC(O)- (Ci-C6)alkyl.
  • R a25 is (Ci-Ce)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 a25 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 a25 is (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -OH, -0(Ci-C6)alkyl, -SFs, -NHC(0)-(Ci-C6)alkyl, and 3- to 6-membered heterocycloalkyl, wherein the
  • R a25 is (C 3 - 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 a25 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-C 6 )alkyl.
  • R a25 is phenyl, wherein the phenyl is
  • R a25 is heteroaryl, wherein the heteroaryl is
  • R a25 is alkynyl. In certain embodiments, R a25 is (C2- C 6 )alkynyl.
  • R a25 is:
  • R a25 is:
  • R a26 and R a27 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-C 6 )cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • R a26 and R a27 attached to the same carbon form an unsubstituted cyclopropyl or cyclobutyl.
  • R a26 and R a27 attached to the same carbon form a cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl are substituted with one or more halo.
  • each R a26 and R a27 is hydrogen.
  • at least one R a26 or R a27 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR a32 , and -NR a33 R a34 .
  • At least one R a26 or R 327 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-C 6 )cycloalkyl, (C 3 -C 6 )halocycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, 3- to 6-membered heteroaryl, -OH, -0-(Ci-C 6 )alkyl, -0-(Ci- C 6 )haloalkyl, -ML ⁇ , -Ml(Ci-C 6 )alkyl, -N((Ci-C 6 )alkyl)((Ci-C 6 )alkyl).
  • substituents independently selected from the group consisting of fluoro, chloro, bromo, (C3-C 6 )cycloalkyl, (C 3 -C 6 )halocycloal
  • one R a26 or one R a27 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 a26 or one R a27 is (Ci-Ce)alkyl, wherein the alkyl is unsubstituted or substituted with fluoro, chloro, (C3-C6)cycloalkyl, (C3)halocycloalkyl, or -OH.
  • one R a26 or one R a27 is ethyl substituted with difluorocyclopropyl.
  • the 4- to lO-membered heterocycloalkyl is a polycyclic heterocycloalkyl.
  • at least one R a26 or R a27 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 326 and R a27 is hydrogen. In other embodiments, q is 2, and one R a26 and two R a27 are hydrogen. In other embodiments, q is 2, and two R a26 and one R a27 are hydrogen. In some embodiments, q is 2, and two R a26 and three R a27 are hydrogen. In some embodiments, q is 2, and three R a26 and two R a27 are hydrogen.
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl.
  • R al is hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocydoalkyl.
  • R al is hydrogen, (Ci-Ce)alkyl, or (C3-C6)cydoalkyl.
  • R al is hydrogen.
  • R al is (Ci-C6)alkyl.
  • R al is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R al is (C3-C6)cydoalkyl.
  • R al is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R a2 is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -SCkR 310 , wherein the alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • each R a7 , R a8 , R a9 is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -SCkR 310 , wherein the alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • each R a7 , R a8 , R a9 , and R al ° is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl.
  • each R a7 , R a8 , R a9 , and R al ° is independently hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered haloheterocycloalkyl.
  • each R a7 , R a8 , R a9 , and R al ° is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, or (C 3 - C6)halocycloalkyl.
  • R a2 is hydrogen, fluoro, chloro, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, -NO2, -CN, -SO2NH2, -NH2, -OH, -0-(Ci-C6)alkyl, -SO2H, or -S02-(Ci-C6)alkyl.
  • R a2 is hydrogen. In some embodiments, wherein R a2 is alkyl, cycloalkyl, or heterocycloalkyl, the alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted. In other embodiments, the alkyl, cycloalkyl, or heterocycloalkyl is substituted with one or more halo. In certain embodiments, the alkyl, cycloalkyl, or heterocycloalkyl is substituted with one to four fluoro, chloro, or bromo, or any combinations thereof.
  • R a3 is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -S02R al °, wherein the alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • each R a7 , R a8 , R a9 , and R al ° is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each R a7 , R a8 , R a9 , and R al °, is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocydoalkyl.
  • R a3 is hydrogen, fluoro, chloro, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, -NO2, -CN, -SO2NH2, -NH2, -NH(Ci-C 6 )alkyl, -N((Ci-C 6 )alkyl)((Ci- Ce)alkyl), -OH, -0-(Ci-C 6 )alkyl, -0-(Ci-C 6 )haloalkyl,
  • R a3 is hydrogen. In some embodiments, wherein R a3 is alkyl, cycloalkyl, or heterocycloalkyl, the alkyl, cycloalkyl, or heterocycloalkyl is un substituted. In other embodiments, the alkyl, cycloalkyl, or heterocycloalkyl is substituted with one or more halo. In certain embodiments, the alkyl, cycloalkyl, or heterocycloalkyl is substituted with one to four fluoro, chloro, or bromo, or any combinations thereof.
  • each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl.
  • each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C 3 - C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, or 3- to 10- membered haloheterocycloalkyl.
  • each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl.
  • each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocycloalkyl.
  • each R a4 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, -NCte, -CN, -SO2NH2, -NH2, -NH(Ci-C6)alkyl, -N((Ci- C6)alkyl)((Ci-C 6 )alkyl),
  • each R a4 is independently selected from the group consisting of fluoro, chloro, bromo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl.
  • At least one R a4 is fluoro, chloro, bromo, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, or -0-(Ci-C6)haloalkyl.
  • at least one R a4 is fluoro, chloro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2, or -CF3.
  • m is an integer from 0 to 13. In some embodiments, m is an integer from 0 to 10. In other embodiments, m is an integer from 0 to 7. In certain embodiments, m is an integer from 0 to 5. In certain embodiments, m is 0, 1, 2, or 3. In still other embodiments, m is an integer from 3 to 13. In further embodiments, m is an integer from 7 to 13. In some embodiments, m is an integer from 3 to 10. In some embodiments, m is 0. In other embodiments, m is 1.
  • p is an integer from 0 to 7. In certain embodiments, p is an integer from 0 to 5. In some embodiments, p is an integer from 3 to 5. In other embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0.
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -S02R al °, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo.
  • R a2 and R a3 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, -NCte, -CN, -SO2NH2, -NH2, -NH(Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, and -OH.
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and -OH. In some embodiments, R a2 and R a3 are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, and -OH. In certain embodiments, R a2 and R a3 are independently hydrogen, methyl, or ethyl. In some embodiments, R a2 and R a3 are both hydrogen. In certain embodiments, one of R 32 and R a3 is (Ci-C 6 )alkyl.
  • R al and R a2 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.
  • the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • heterocycloalkyl is unsubstituted.
  • two to four R a4 together with the atoms to which they are attached, form a (C 6 -Cio)aryl, 3- to 6-membered heteroaryl, (C3-C 6 )cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is fused with ring A.
  • the cycloalkyl or heterocycloalkyl forms a spirocyclic system with ring A.
  • R a4 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; there may exist one or more other R a4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN,
  • R a2 and one R a4 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 a2 and one R a4 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 a2 and one R a4 , 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
  • the heterocycloalkyl is unsubstituted.
  • R a2 and one R a4 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 32 and R a4 may be fused to ring A.
  • R a2 and one R a4 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 32 and R a4 may be fused to ring A.
  • R 32 and R a4 may be fused to ring A.
  • R 3 is hydrogen
  • R a3 and one R a4 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 a3 and one R a4 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 a3 and one R a4 , 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. In certain embodiments, R a3 and one R a4 , together with the atoms to which they are attached, form a C3-cycloalkyl. The cycloalkyl or
  • heterocycloalkyl formed by R a3 and R a4 may be fused to ring A.
  • R a3 and R a4 may be fused to ring A.
  • R a2 is hydrogen
  • R a2 or R a3 is hydrogen. In other embodiments, both of R a2 and R a3 are hydrogen. In some embodiments, m is 0. Thus, in some embodiments,
  • R al and one R a4 together with the atoms to which they are attached, form a spirocycle with ring A.
  • the spirocycle is unsubstituted.
  • the spirocycle is substituted with one or more halo.
  • R a2 and one R a4 together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein R a3 and one R a4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl; or wherein two to four R a4 , together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; there may exist one or more other R a4 independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCte, -CN, -SO2NH2, -NR a
  • m is 3; R a2 and one R a4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining two R a4 are independently halo or alkyl.
  • p is 4; R a3 and one R a4 , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining three R a4 are independently -OH, halo, alkyl, or haloalkyl.
  • R a2 and R a3 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 a2 and R a3 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. In some embodiments, the cycloalkyl is unsubstituted. In other embodiments, R a2 and R a3 , 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.
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- .
  • X is -S(0) 2- , -C(O)-, or -C(R a6 ) 2- . In certain embodiments, X is -S(O)-, -S(0) 2- , or -S(0)NR a46 -. In other embodiments, X is -C(S)-, -C(O)-, or -C(R a6 ) 2-
  • X is -S(O)-.
  • R a46 is hydrogen.
  • R a46 is unsubstituted (Ci-Ce)alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • X is -C(S)-.
  • X is -C(O)-.
  • X is -C(R a6 )2-, wherein each R a6 is independently hydrogen, halo, alkyl, or haloalkyl.
  • each R a6 is independently hydrogen, halo, (Ci-Ce)alkyl, or (Ci-C 6 )haloalkyl. In some embodiments, each R a6 is independently hydrogen, chloro, fluoro, methyl, ethyl, propyl, -CFhF, -CHF2, or -CF 3. In some embodiments, each R a6 is H, and X is -CH2-.
  • X is -S(0)2-, -C(O)-, or -CH2-.
  • the compound of Formula (I), Formula (I-A), Formula (I-A- i), Formula (I-B), or Formula (I-B-i) is:
  • the compound of Formula (X), Formula (X-I), Formula (X- A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i) is:
  • the compound of Formula (I), Formula (I-A), Formula (I-A- i), Formula (I-B), or Formula (I-B-i), is:
  • the compound of Formula (X), Formula (X-I), Formula (X- A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i) is:
  • the compounds described herein including compounds of Formula (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or their 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 (S)- .
  • Optically active (+) and (-), or ( R )- and fV)-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-performance liquid chromatography (HPLC).
  • “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- lO-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- l,2-disulfonic acid, ethanesulfonic acid, 2- hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic
  • 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 diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, or N- ethylpiperidine.
  • a compound provided herein including compounds of Formula (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X- C), Formula (X-C-i), Formula (I), Formula (I- A), Formula (I-A-i), Formula (I-B), Formula (I- B-i), Formula (I-C), or Formula (I-C-i), and including any of the species provided herein, is a hydrochloric acid salt.
  • the compounds provided herein including compounds of Formula (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X- C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I- B-i), Formula (I-C), or their 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 ⁇ 4), or the replacement of a carbon- 12 by a carbon-l3 ( 13 C) or carbon-l4 ( 14 C).
  • the compounds disclosed herein such as a compound of Formula (X), Formula (X- I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a pharmaceutically acceptable salt thereof, may be prepared, for example, through the reaction routes depicted in General Scheme 1-1.
  • General Scheme 1-1 provides three routes to prepare a compound disclosed herein, such as a compound of Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof.
  • compound I- 102 is combined with 2-chloroethanesulfony chloride, triethylamine (Et 3 N), and solvent (such as dichloromethane, DCM), and that mixture is stirred from 0 °C to room temperature to produce compound 1-104.
  • This compound is then combined with trifluoroacetic acid (TFA) and solvent (such as DCM) and stirred from 0 °C to room temperature to remove the BOC protecting group and produce compound 1-106.
  • TFA trifluoroacetic acid
  • solvent such as DCM
  • This compound can be combined with triethylamine, solvent (such as DCM), and an R B -carbonyl chloride reactant, wherein the R B is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
  • This mixture is then stirred at room temperature to produce compound 1-108, an example of a compound of Formula (I), Formula (I- A), Formula (I-A-i), Formula (I-B), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • compound 1-106 may be combined with triethylamine, solvent (such as DCM), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid
  • compound 1-106 is combined with triethylamine, a solvent (such as DCM), and an R B -S02Cl reactant and stirred at room temperature to produce compound 1-110, an example of a compound of Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
  • a different solvent is used in one or more steps, such acetonitrile.
  • a different amine is used.
  • the temperature may be adjusted.
  • a pharmaceutical composition comprising a compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X- C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I- B-i), Formula (I-C), or Formula (I-C-i), or a 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.
  • 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 (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a 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.
  • 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.
  • the disorder is related mutation or dysregulation of human K-Ras4b.
  • the disorder is related to aberrant K-Ras4b signaling pathway activity. In some embodiments, the disorder is related mutation or dysregulation of human K-Ras4a. In certain embodiments, the disorder is related to aberrant K-Ras4a signaling pathway activity.
  • the disorder is neurofibromatosis type 1 (NF1), Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • the disorder is neurofibromatosis type 1 (NF1).
  • 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 mutation or dysregulation of human K-Ras4b.
  • the cancer is related to aberrant K-Ras4b signaling pathway activity.
  • the cancer is related mutation or dysregulation of human K-Ras4a.
  • the cancer is related to aberrant K-Ras4a 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 (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I- A), Formula (I-A- i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a 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 (X), Formula (X-I), Formula (X- A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a 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 (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a pharmaceutically acceptable salt thereof.
  • the K-Ras protein is human K-Ras4a and/or human K-Ras4b.
  • the K-Ras is human K-Ras4b. In certain embodiments, the K-Ras is human K-Ras4a. 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 (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a 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.
  • a K-Ras precursor such as K-Ras4a precursor or K-Ras4b precursor
  • the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a pharmaceutically acceptable salt thereof covalently binds to the Cl 85 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.
  • 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 (X), Formula (X-I), Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I), Formula (I-A), Formula (I-A-i), Formula (I-B), Formula (I-B-i), Formula (I-C), or Formula (I-C-i), or a pharmaceutically acceptable salt thereof.
  • the K-Ras protein is human K-Ras4a and/or human K-Ras4b. In certain embodiments, the K-Ras is human K-Ras4b. In certain embodiments, the K-Ras is human K-Ras4a.
  • both the activity of K-Ras and the level of K-Ras are reduced in a subject in need thereof.
  • the K-Ras is human K-Ras4b.
  • the K-Ras is human K-Ras4a.
  • 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, or 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, 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 1-1 A compound of Formula (I):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • each R a6 is independently hydrogen, halo, alkyl, or haloalkyl
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -S02R al °, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R a3 and one R a4 , 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; or R al and R a2 , together with the atoms to which they are attached, form a
  • each R a5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a22 , R a23 , R a24 , R a36 , R a37 , R a38 , R a39 , and R a40 is independently hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11.
  • Embodiment 1-2 The compound of Embodiment 1-1, or a pharmaceutically acceptable salt thereof, wherein:
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • each R a6 is independently hydrogen, halo, alkyl, or haloalkyl
  • R al is hydrogen, alkyl, or cycloalkyl, wherein when R al is alkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N0 2 , -CN, -SOzNTL ⁇ , -NR a7 R a8 , -OR a9 , and -S0 2 R al °, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N0 2 , -CN, -S0 2 NH 2 ,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl, or halocycloalkyl or two to four R a4 , together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or R a2 and one R a4 , together with the atoms to which they are attached, form a
  • heterocycloalkyl or R a2 and R a3 , together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl; or, when X is -S(O)-, -S(0)2-, -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl; each R a5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each R al1 , R al2 , R al9 , R a20 , and R a21 is independently hydrogen, alkyl,
  • Embodiment 1-3 The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (I- A):
  • Embodiment 1-4 The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (I-B):
  • Y is -C(R a45 )2-,— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • r 0, 1, or 2;
  • p is an integer from 0 to 7;
  • Embodiment 1-5 The compound of Embodiment 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is -CEh-
  • Embodiment 1-6 The compound of Embodiment 1-1 or 1-2, or a pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
  • Embodiment 1-7 The compound of any one of Embodiments 1-1 to 1-6, or a pharmaceutically acceptable salt thereof, wherein B is heteroaryl, cycloalkyl, or
  • Embodiment 1-8 The compound of any one of Embodiments 1-1 to 1-7, or a pharmaceutically acceptable salt thereof, wherein B is 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment 1-9 The compound of any one of Embodiments 1-1 to 1-7, or a pharmaceutically acceptable salt thereof, wherein B is 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment 1-10 The compound of any one of Embodiments 1-1 to 1-6, or a pharmaceutically acceptable salt thereof, wherein B is (C9-Cio)bicyclic aryl.
  • Embodiment 1-11 The compound of any one of Embodiments 1-1 to 1-7, or a pharmaceutically acceptable salt thereof, wherein B is (C5-Cio)cycloalkyl.
  • Embodiment 1-12 The compound of any one of Embodiments 1-1 to I- 11 , or a pharmaceutically acceptable salt thereof, wherein one or more R a5 are independently selected from the group consisting of halo; -0-(Ci-C 4 )alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C 3 - C 6 )cycloalkyl unsubstituted or substituted with one or more fluoro or chloro; and (Ci- C 6 )alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C 6 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, aryl, heteroaryl, halo, -OH, -0-(Ci-C 4 )
  • Embodiment 1-14 The compound of any one of Embodiments 1-1 to 1-13, or a pharmaceutically acceptable salt thereof, wherein at least one of R a5 is:
  • R a25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R a2X , R a29 , R a30 , R a31 , R a32 , R a33 , R a34 , R a41 , R a42 , R a43 , and R a44 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
  • Embodiment 1-15 The compound of Embodiment 1-14, or a pharmaceutically acceptable salt thereof, wherein q is 1 and R a26 is hydrogen.
  • Embodiment 1-16 The compound of any one of Embodiments 1-1 to 1-15, or a pharmaceutically acceptable salt thereof, wherein at least one R a5 is heteroaryl or
  • Embodiment 1-17 The compound of Embodiment 1-14, or a pharmaceutically acceptable salt thereof, wherein R a35 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
  • Embodiment 1-18 The compound of any one of Embodiments 1-1 to 1-17, or a pharmaceutically acceptable salt thereof, wherein R a2 and R a3 , together with the atom to which they are attached, form a (C3-Cs)cycloalkyl or a 3- to 5-membered heterocycloalkyl.
  • Embodiment 1-19 The compound of any one of Embodiments 1-1 to 1-17, or a pharmaceutically acceptable salt thereof, wherein X is -S(0)2-, and R al and one R a4 , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
  • Embodiment 1-20 The compound of any one of Embodiments 1-1 to 1-17, or a pharmaceutically acceptable salt thereof, wherein R a2 and one R a4 , together with the atoms to which they are attached, form a (C3-C6)cycloalkyl or a 3- to 6-membered heterocycloalkyl.
  • Embodiment 1-21 The compound of any one of Embodiments 1-1 to 1-17, or 1-19, or a pharmaceutically acceptable salt thereof, wherein R a2 and R a3 are each hydrogen.
  • Embodiment 1-22 The compound of any one of Embodiments 1-1 to 1-21, or a pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
  • Embodiment 1-2 The compound of any one of Embodiments 1-1 to 1-18, 1-20, or 1-21, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • Embodiment 1-24 The compound of any one of Embodiments 1-1 to 1-18, 1-20, or
  • Embodiment 1-25 The compound of any one of Embodiments 1-1 to 1-12 or 1-14 to 1-24, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  • Embodiment 1-26 The compound of any one of Embodiments 1-1, 1-2, 1-6 to 1-12, or 1-14 to 1-25, or a pharmaceutically acceptable salt thereof, wherein m is 0.
  • Embodiment 1-27 The compound of any one of Embodiments 1-3 to 1-5, or 1-7 to I- 26, or a pharmaceutically acceptable salt thereof, wherein p is 0.
  • Embodiment 1-28 The compound of any one of Embodiments 1-1 to 1-6, 1-12, or I- 14 to 1-26, or a pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
  • Embodiment 1-29. The compound of any one of Embodiments 1-1, 1-2, 1-12, and I- 14 to 1-17, or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heterocycloalkyl, B is phenyl, and n is an integer from 0 to 5.
  • Embodiment 1-30 A compound of Embodiment 1-1, wherein the compound is:
  • Embodiment 1-3 A pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-32 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 1-30, or a pharmaceutically acceptable sat thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-33 The method of Embodiment 1-32, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-34 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 1-30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-35 The method of Embodiment 1-34, wherein the disorder is cancer.
  • Embodiment 1-36 The method of Embodiment 1-35, 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 1-37 The method of Embodiment 1-34, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-38 The method of any one of Embodiments 1-34 to 1-37, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment 1-39 ETse of a compound of any one of Embodiments 1-1 to 1-30, or a 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 1-40 The use of Embodiment 1-39, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-4 ETse of a compound of any one of Embodiments 1-1 to 1-30, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
  • Embodiment 1-42 The use of Embodiment 1-41, wherein the disorder is cancer.
  • Embodiment 1-43 The use 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 use of Embodiment 1-41, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-45 The use of any one of Embodiments 1-41 to 1-44, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment 1-46 A compound according to any one of Embodiments 1-1 to 1-30, or a 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 1-47 The compound for use of Embodiment 1-46, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-48 A compound according to any one of Embodiments 1-1 to 1-30, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
  • Embodiment 1-49 The compound for use in Embodiment 1-48, wherein the disorder is cancer.
  • Embodiment 1-50 The compound for 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 compound for 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 compound for use of any one of Embodiments 1-48 to 1-51, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment II-1 A compound of Formula (X):
  • R xl , R x2 , and R x3 are independently hydrogen, -CN, or alkyl; or R x2 and R x3 together form alkenyl; or R xl and R x2 together with the carbon atoms to which they are attached form heteroaryl, heterocycloalkenyl, or cycloalkenyl; or R al and R x2 together with the atoms to which they are attached form heterocycloalkenyl; wherein each alkyl, alkenyl, heteroaryl, heterocycloalkenyl, and cycloalkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and -OR x4 , wherein each R x4 is independently H, alkyl, or haloalkyl;
  • A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • X is -S(O)-, -S(0) 2- -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ; each R a6 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -S02R al °, wherein when A is phenyl, R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, cycloalkyl,
  • heterocycloalkyl -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , and -S0 2 R al °; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently
  • each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR a7 R a8 , -OR a9 , 0, -SR a47 , and -SCkR 310 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R a3 and one R a4 , 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; or R al and R a2 , together with the atoms to which they are attached, form a
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or R a2 and R a3 , 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; or, when X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; or, when X is -C(O)-, R al and one R a4 , together with the atoms to which they are attached, form a spirocycle with ring A, wherein the spirocycle is
  • each R a5 is independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -N0 2 , -CN,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a50 , R a51 , R a52 , R a53 , R a54 , R a55 , R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R al1 , R al2 , R al3 , R al6 , R al7 , R al8 , R al9 , R a20 , R 321 , R a35 , R a54 , and R a55 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R a58 is independently unsubstituted or substituted with one or more substituents independently selected from
  • each R a22 , R a23 , R a24 , R a36 , R a37 , R a38 , and R a39 is independently hydrogen, alkyl, or haloalkyl;
  • each alkyl or haloalkyl or R a22 and R a23 is independently
  • each R a40 is independently hydrogen, alkyl, haloalkyl, aryl, or heteroaryl, wherein each aryl or heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
  • n is an integer from 0 to 13;
  • Embodiment II-2 The compound of Embodiment II- 1, wherein the compound is of Formula (X-I):
  • A is 4- to lO-membered heterocycloalkyl
  • B, X, R xl , R x2 , R x3 , R al , R 32 , R a3 , R a4 , R a5 , m, and n are as defined for Formula (X).
  • Embodiment II-3 The compound of Embodiment II- 1 or II-2, wherein the compound is of Formula (X-A):
  • Embodiment II-4 The compound of Embodiment II-1 or II-2, wherein the compound is of Formula (X-C):
  • Embodiment II-5 The compound of Embodiment II- 1 or II-2, wherein the compound is of Formula (X-B):
  • Y is -C(R a45 )2-,— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ‘)2— , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • Embodiment II-6 The compound of Embodiment II- 1, wherein the compound is of Formula (I):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ;
  • each R a6 is independently hydrogen, halo, alkyl, or haloalkyl
  • R al is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when R al is alkyl or haloalkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N0 2 , -CN, -SOzNEb, -NR a7 R a8 , -OR a9 , and -S0 2 R al °, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N0 2 , -CN, -SOzNEb, -NR a7 R a8 , -OR a9 , 0, -SR a47 , and -S0 2 R al °, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four R a4 , together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or
  • cycloalkyl or heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or R a3 and one R a4 , 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; or R al and R a2 , together with the atoms to which they are attached, form a
  • R a2 and R a3 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; or, when X is -S(O)-, -S(0)2-, -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each R a5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • X is -S(O)-, -S(0)2-, -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ; each R a6 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R al is hydrogen, alkyl, or cycloalkyl, wherein when R al is alkyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(O)-;
  • R a2 and R a3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N0 2 , -CN, -SOzNEb, -NR a7 R a8 , -OR a9 , and -S0 2 R al °, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R a4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N0 2 , -CN, -SOzNEb, -NR a7 R a8 , -OR a9 , 0, -SR a47 , and -S0 2 R al °, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each R a7 , R a8 , R a9 , R al °, and R a47 is independently hydrogen, alkyl, haloalkyl,
  • cycloalkyl, or halocycloalkyl or two to four R a4 , together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or R a2 and one R a4 , together with the atoms to which they are attached, form a
  • heterocycloalkyl or R a2 and R a3 , together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl; or, when X is -S(O)-, -S(0)2-, -S(0)NR a46 -, or -C(S)-, R al and one R a4 , together with the atoms to which they are attached, form a heterocycloalkyl; each R a5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R a58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R a56 , and R a57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each R al1 , R al2 , R al9 , R a20 , and R a21 is independently hydrogen, alkyl,
  • each R al3 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R al 1 , R al2 , R al3 , R al9 , R a20 , R a21 , and R a35 , and each cycloalkyl,
  • heterocycloalkyl, aryl, and heteroaryl of R a58 is independently unsubstituted or substituted with one or more substituents
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • Embodiment II-8 The compound of Embodiment II-6 or II-7, wherein the compound is of Formula (I- A):
  • Embodiment II-9 The compound of Embodiment II-6 or II-7, wherein the compound is of Formula (I-B):
  • Y is -C(R a45 ) 2- ,— S(0)r— , -0-, or -N(R a45 )-, wherein each R a45 is independently hydrogen or R a4 ;
  • X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, -C(O)-, or -C(R a6 ) 2- , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0) 2- , -S(0)NR a46 -, -C(S)-, or -C(R a6 ) 2- ; r is 0, 1, or 2; p is an integer from 0 to 7; and B, R al , R a2 , R a3 , R a4 , R a5 , R a6 , R a46 , and n are as defined for Formula (I).
  • Embodiment II- 10 The compound of Embodiment II-5 or II-9, or a
  • Embodiment II- 11 The compound of any one of Embodiments II- 1, II-2, II-6, or II-7, or a pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
  • Embodiment 11-12 The compound of Embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heteroaryl.
  • Embodiment 11-13 The compound of any one of Embodiments II- 1 to 11-12, or a pharmaceutically acceptable salt thereof, wherein B is heteroaryl, cycloalkyl, or
  • Embodiment 11-14 The compound of any one of Embodiments II- 1 to 11-13, or a pharmaceutically acceptable salt thereof, wherein B is 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, and wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment 11-15 The compound of any one of Embodiments II- 1 to 11-13, or a pharmaceutically acceptable salt thereof, wherein B is 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment 11-16 The compound of any one of Embodiments II- 1 to 11-12, or a pharmaceutically acceptable salt thereof, wherein B is (C9-Cio)bicyclic aryl.
  • Embodiment 11-17 The compound of any one of Embodiments II- 1 to 11-13, or a pharmaceutically acceptable salt thereof, wherein B is (C5-Cio)cycloalkyl.
  • Embodiment 11-18 The compound of any one of Embodiments II- 1 to 11-12, or a pharmaceutically acceptable salt thereof, wherein B is phenyl.
  • Embodiment 11-19 The compound of any one of Embodiments II- 1 to 11-18, or a pharmaceutically acceptable salt thereof, wherein at least one R a5 is:
  • Embodiment 11-20 The compound of Embodiment 11-19, or a pharmaceutically acceptable salt thereof, wherein both R al1 and R al2 are not hydrogen.
  • Embodiment 11-21 The compound of Embodiment 11-19 or 11-20, or a
  • Embodiment 11-22 The compound of any one of Embodiments 11-19 to 11-21, or a pharmaceutically acceptable salt thereof, wherein R al1 is alkyl substituted with aryl, wherein the aryl is unsubstituted or substituted.
  • Embodiment 11-24 The compound of Embodiment 11-19, or a pharmaceutically acceptable salt thereof, wherein at least one R a5 is Ci-alkyl substituted with -NR a20 R a2 1 , wherein at least one of R a20 and R a21 is not hydrogen.
  • each alkyl is independently unsubstituted or substituted with one or more halo.
  • Embodiment 11-28 The compound of Embodiment 11-27, or a pharmaceutically acceptable salt thereof, wherein both R a20 and R a21 are not hydrogen.
  • Embodiment 11-29 The compound of any one of Embodiments II- 1 to 11-18, or a pharmaceutically acceptable salt thereof, wherein one or more R a5 is -NR all R a12 , wherein:
  • R al1 is Ci-alkyl substituted with aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, and haloalkyl.
  • Embodiment 11-30 The compound of any one of Embodiments II- 1 to 11-18, or a pharmaceutically acceptable salt thereof, wherein one or more R a5 is a substituted alkyl of formula (a):
  • w is 0 or 1;
  • R a20 and R a21 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl,
  • each alkyl is independently unsubstituted or substituted with one or more halo.
  • Embodiment 11-32 The compound of Embodiment II-31, or a pharmaceutically acceptable salt thereof, wherein one terminal methyl of the isopropyl is substituted with phenyl, wherein the phenyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of halo and haloalkyl.
  • Embodiment 11-33 The compound of Embodiment II-31 or 11-32, or a
  • Embodiment 11-35 The compound of any one of Embodiments II- 1 to II-3 or 11-19 to 11-34, wherein the compound is of Formula (X-A-i):
  • R xl , R x2 , R x3 , R al , R a2 , R a3 , R a4 , and R a5 are as defined in Formula (X).
  • Embodiment 11-36 The compound of any one of Embodiments II-6 to II-8 or 11-19 to 11-34, wherein the compound is of Formula (I-A-i):
  • Embodiment 11-37 The compound of any one of Embodiments II- 1 , II-2, II-4, or 11-19 to 11-34, wherein the compound is of Formula (X-C-i):
  • R xl , R x2 , R x3 , R al , R a2 , R a3 , R a4 , and R a5 are as defined in Formula (X).
  • Embodiment 11-38 The compound of any one of Embodiments II- 1 to 11-18 or II- 34 to 11-37, or a pharmaceutically acceptable salt thereof, wherein at least one of R a5 is:
  • R a25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R a26 and R a27 is independently hydrogen, halo, or alkyl; wherein 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 a32 , and
  • Embodiment 11-39 The compound of Embodiment 11-38, or a pharmaceutically acceptable salt thereof, wherein q is 1 and R a26 is hydrogen.
  • Embodiment 11-41 The compound of Embodiment 11-40, or a pharmaceutically acceptable salt thereof, wherein R a35 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
  • Embodiment 11-42 The compound of any one of Embodiments II- 1 to 11-41, or a pharmaceutically acceptable salt thereof, wherein R a2 and R a3 , together with the atom to which they are attached, form a (C3-Cs)cycloalkyl or a 3- to 5-membered heterocycloalkyl.
  • Embodiment 11-43 The compound of any one of Embodiments II- 1 to 11-41, or a pharmaceutically acceptable salt thereof, wherein X is -S(0)2-, and R al and one R a4 , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
  • Embodiment 11-44 The compound of any one of Embodiments II- 1 to 11-41, or a pharmaceutically acceptable salt thereof, wherein R a2 and one R a4 , together with the atoms to which they are attached, form a (C3-C6)cycloalkyl or a 3- to 6-membered heterocycloalkyl.
  • Embodiment 11-45 The compound of any one of Embodiments II- 1 to 11-41, or II- 43, or a pharmaceutically acceptable salt thereof, wherein R a2 and R a3 are each hydrogen.
  • Embodiment 11-46 The compound of any one of Embodiments II- 1 to 11-42, 11-44, or 11-45, or a pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
  • Embodiment 11-47 The compound of any one of Embodiments II- 1 to 11-42, 11-44, or 11-45, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • Embodiment 11-48 The compound of any one of Embodiments II- 1 to 11-42, 11-44, or 11-45, or a pharmaceutically acceptable salt thereof, wherein X is -CEh-
  • Embodiment 11-49 The compound of any one of Embodiments II- 1 to 11-34 or II- 38 to 11-48, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  • Embodiment 11-50 The compound of any one of Embodiments II- 1, II-2, II-6, II-7, II- 11 to 11-34, or 11-38 to 11-49, or a pharmaceutically acceptable salt thereof, wherein m is 0.
  • Embodiment 11-51 The compound of any one of Embodiments II-3 to II-5, II-8 to II- 10, or 11-13 to 11-49, or a pharmaceutically acceptable salt thereof, wherein p is 0.
  • Embodiment 11-52 The compound of any one of Embodiments II- 1 to 11-12, 11-19 to 11-34, 11-38 to 11-48, 11-50, or 11-51, or a pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
  • Embodiment 11-53 The compound of any one of Embodiments II- 1, II-2, II-6, II-7, 11-19 to 11-34, or 11-38 to 11-41, or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heterocycloalkyl, B is phenyl, and n is an integer from 0 to 5.
  • Embodiment 11-54 The compound of any one of Embodiments II- 1 to II-5, II- 10 to 11-35, or 11-37 to 11-53, or a pharmaceutically acceptable salt thereof, wherein R xl is hydrogen.
  • Embodiment 11-55 The compound of any one of Embodiments II- 1 to II-5, II- 10 to 11-35, 11-37 to 11-54, or a pharmaceutically acceptable salt thereof, wherein R x2 and R x3 are hydrogen.
  • Embodiment 11-56 The compound of any one of Embodiments II- 1 to II-5, II- 10 to 11-35, or 11-37 to 11-55, or a pharmaceutically acceptable salt thereof, wherein one of R xl , R x2 , and R x3 is unsubstituted or substituted alkyl.
  • Embodiment 11-57 The compound of Embodiment II- 1, wherein the compound is:
  • Embodiment 11-58 The compound of Embodiment II- 1 or II-6, wherein the compound is:
  • Embodiment 11-59 The compound of Embodiment II- 1 or II-6, wherein the compound is:
  • Embodiment 11-60 The compound of Embodiment II- 1, wherein the compound is:
  • Embodiment 11-61 A pharmaceutical composition comprising a compound according to any one of Embodiments II- 1 to 11-60, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 11-62 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 II- 1 to 11-60, or a pharmaceutically acceptable sat thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 11-63 The method of Embodiment 11-62, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment II-63-ii The use of Embodiment 11-62, wherein the K-Ras protein is human K-Ras4a.
  • Embodiment 11-64 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 II- 1 to 11-60, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 11-65 The method of Embodiment 11-64, wherein the disorder is cancer.
  • Embodiment 11-66 The method of Embodiment 11-65, 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 11-67 The method of Embodiment 11-64, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 11-68 The method of any one of Embodiments 11-64 to 11-67, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment 11-69 ETse of a compound of any one of Embodiments II- 1 to 11-60, or a 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 11-70 The use of Embodiment 11-69, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment II-70-ii The use of Embodiment 11-69, wherein the K-Ras protein is human K-Ras4a.
  • Embodiment 11-71 ETse of a compound of any one of Embodiments II- 1 to 11-60, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
  • Embodiment 11-72 The use of Embodiment 11-71, wherein the disorder is cancer.
  • Embodiment 11-73 The use of Embodiment 11-72, 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 11-74 The use of Embodiment 11-71, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 11-75 The use of any one of Embodiments 11-71 to 11-74, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment 11-76 A compound according to any one of Embodiments II- 1 to II- 60, or a 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 11-77 The compound for use of Embodiment 11-76, wherein the K- Ras protein is human K-Ras4b.
  • Embodiment II-77-ii The use of Embodiment 11-76, wherein the K-Ras protein is human K-Ras4a.
  • Embodiment 11-78 A compound according to any one of Embodiments II- 1 to II- 60, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
  • Embodiment 11-79 The compound for use in Embodiment 11-78, wherein the disorder is cancer.
  • Embodiment 11-80 The compound for use of Embodiment 11-79, 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 11-81 The compound for use of Embodiment 11-78, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 11-82 The compound for use of any one of Embodiments 11-78 to II- 81, wherein the disorder is associated with a mutation of K-Ras.
  • Example 1-3 Synthesis of Formula (I) compounds comprising a pyrrolidinyl, heteroaryl, and carbonyl linker

Abstract

L'invention concerne des composés comprenant une fraction sulfonamide de vinyle. L'invention concerne également des compositions pharmaceutiques comprenant de tels composés, et des procédés d'utilisation de tels 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/US2019/027959 2018-04-18 2019-04-17 Modulateurs de k-ras avec une fraction de sulfonamide de vinyle WO2019204505A2 (fr)

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Cited By (6)

* 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
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022117882A3 (fr) * 2020-12-03 2022-07-07 Domain Therapeutics Nouveaux inhibiteurs de par-2
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
WO2024020101A1 (fr) * 2022-07-21 2024-01-25 The Regents Of The University Of California Composés inhibiteurs de la prostaglandine e synthase 3 (ptges3)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3526638A (en) * 1967-10-05 1970-09-01 Smithkline Corp Substituted 3,4-dihydro-1h-2,1,5-benzothiadiazocine-2,2-dioxides
CA2552558A1 (fr) * 2004-01-16 2005-08-11 Wyeth Inhibiteurs a base de sulfonamides heterocycliques de la production des beta-amyloides contenant un azole
JP5374157B2 (ja) * 2005-11-24 2013-12-25 ドムペ・ファ．ル．マ・ソチエタ・ペル・アツィオーニ （ｒ）−アリールアルキルアミノ誘導体類と、それらを含有する薬剤組成物
TW200831092A (en) * 2006-12-21 2008-08-01 Astrazeneca Ab Therapeutic agents
US9227978B2 (en) * 2013-03-15 2016-01-05 Araxes Pharma Llc Covalent inhibitors of Kras G12C
EP2970121B1 (fr) * 2013-03-15 2017-12-13 Araxes Pharma LLC Inhibiteurs covalents de k-ras g12c
WO2016179558A1 (fr) * 2015-05-06 2016-11-10 The Regents Of The University Of California Modulateurs de k-ras
US9890163B2 (en) * 2015-10-15 2018-02-13 Princeton Drug Discovery Inc Inhibitors of protein kinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
US11760728B2 (en) 2019-05-31 2023-09-19 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
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
WO2022117882A3 (fr) * 2020-12-03 2022-07-07 Domain Therapeutics Nouveaux inhibiteurs de par-2
WO2024020101A1 (fr) * 2022-07-21 2024-01-25 The Regents Of The University Of California Composés inhibiteurs de la prostaglandine e synthase 3 (ptges3)

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