WO2019204505A2 - K-ras modulators with a vinyl sulfonamide moiety - Google Patents

K-ras modulators with a vinyl sulfonamide moiety Download PDF

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Publication number
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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French (fr)
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WO2019204505A3 (en
Inventor
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/en
Publication of WO2019204505A3 publication Critical patent/WO2019204505A3/en

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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
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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
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    • 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
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    • 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

Provided herein are compounds comprising a vinyl sulfonamide moiety. Also provided herein are pharmaceutical compositions comprising such compounds, and methods of using such compounds and pharmaceutical compositions for inhibiting the post-translational processing of K-Ras precursors, and for treating disorders in a subject in need thereof.

Description

K-RAS MODULATORS WITH A VINYL SULFONAMIDE MOIETY
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 62/659,607, filed April 18, 2018, the disclosure of which is hereby incorporated herein by reference in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
[0002] This invention was made with government support under Contract No.
HHSN261200800001E awarded by the National Institutes of Health. The government has certain rights in the invention.
FIELD
[0003] 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.
BACKGROUND
[0004] 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.
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. BRIEF SUMMARY
[0005] In some aspects, provided herein is a compound of Formula (X):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rxl, Rx2, and Rx3 are independently hydrogen, -CN, or alkyl; or Rx2 and Rx3 together form alkenyl; or Rxl and Rx2 together with the carbon atoms to which they are attached form heterocycloalkenyl or cycloalkenyl; or Ral and Rx2 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 -ORx4, wherein each Rx4 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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-; Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -SCkR310, wherein when A is phenyl, Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, cycloalkyl,
heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently
unsubstituted or substituted with one or more halo;
each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2,
-NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, 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)-, Ral and one Ra4, together with the atoms to which they are attached, form a spirocycle with ring A, wherein the spirocycle is
unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15,
wherein 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, -ORa16, =0, -NRal7Ral8,-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Ral 1 Ral2 Ral3 Ral4 J^al5 Ral6 Ral7 Ral8 Ral9 J^a20 J^a2l j^a48 j^a49
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, Ra35, Ra54, and Ra55, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra23, -ORa24, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently
selected from the group consisting of =0, -ML·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, and Ra39 is independently hydrogen, alkyl, or haloalkyl; wherein each alkyl or haloalkyl or Ra22 and Ra23 is independently
unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which 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 Ra40 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 1 1.
[0006] In some variations, the compound of Formula (X) is a compound of Formula (X-I):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein A is 4- to lO-membered heterocycloalkyl, and B, X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, Ra5, m, and n are as defined for Formula (X).
[0007] In some variations, the compound of Formula (X) is a compound of Formula (X-A):
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (X).
[0008] In some variations, the compound of Formula (X) is a compound of Formula (X-C):
Figure imgf000008_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (X).
[0009] In some variations, the compound of Formula (X) is a compound of Formula (X-B):
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2- -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6 ‘)2— , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
r is 0, 1, or 2; p is an integer from 0 to 7; and B, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (X).
[0010] In some variations, the compound of Formula (X) is a compound of Formula (X-A- i):
Figure imgf000009_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X). [0011] In some variations, the compound of Formula (X) is a compound of Formula (X-C- i):
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X).
[0012] In some aspects, the compound of Formula (X) is a compound of Formula (I):
Figure imgf000010_0002
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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0; Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2,
-NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15,
wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52,
-S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Ral 1 Ral2 Ral3 Ral4 J^al5 Ral6 Ral7 Ral8 Ral9 J^a20 j^a2l j^a48 j^a49
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra23, -ORa24, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently
selected from the group consisting of =0, -NH2, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; and n is an integer from 0 to 1 1.
[0013] In some variations of the compound of Formula (X), Formula (X-I), or Formula (I), or a pharmaceutically acceptable salt thereof, A is 5- or 6-membered heterocycloalkyl.
[0014] In some variations, the compound of Formula (X) or Formula (I) is a compound of Formula (I- A):
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (I).
[0015] In other variations, the compound of Formula (X) or Formula (I) is a compound of Formula (I-B):
Figure imgf000013_0002
or a pharmaceutically acceptable salt thereof, wherein: Y is -C(Ra45)2-— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2- -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2- wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; r is 0, 1, or 2; p is an integer from 0 to 7; and B, Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (I).
[0016] In certain variations of the compound of Formula (I-B), or a pharmaceutically acceptable salt thereof, Y is -CFh- In certain variations of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), or Formula (I-B), or a pharmaceutically acceptable salt thereof, B is heteroaryl, cycloalkyl, or heterocycloalkyl.
[0017] In other variations, the compound of Formula (X) or Formula (I) is a compound of Formula (I-A-i):
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and X, R a, Ra2, Ra3, Ra4, and Ra5 are as defined for Formula (I).
[0018] In certain variations of 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), or Formula (I-B), or a pharmaceutically acceptable salt thereof, at least one of Ra5 is:
Figure imgf000015_0001
wherein:
Ra25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORa28, -SFs, and
-NRa29Ra30;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -SFs, =0, -ORa31,
-NRa41Ra42, -NRa43C(0)Ra44, cycloalkyl, and heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, halo, -OH, and -SFs;
each Ra26 and Ra27 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, -ORa32, and - NRa33Ra34;
wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =0, and -SFs; or one Ra26 and one R327 attached to the same atom, 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 Ra2X, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra41, Ra42, Ra43, and Ra44 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
[0019] In certain variations of 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), or Formula (I-B), or a pharmaceutically acceptable salt thereof, X is — S(0)2— . In other variations, X is -C(O)-. In still further variations, X is -CFh-
[0020] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (X) (such as Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some variations, 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.
[0021] In a further aspect, provided herein is 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. In some variations, 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.
[0022] In still another aspect, provided herein is 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. In some variations, 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.
[0023] In yet a further aspect, provided herein is the use of 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. In some variations, 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.
[0024] In another aspect, provided herein is the use of 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. In some variations, 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.
[0025] In still a further aspect, provided herein is 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. In some variations, 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.
[0026] In yet another aspect, provided herein is 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. In some variations, 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.
[0027] In certain variations of the aspects described herein, the disorder is cancer. In some embodiments, the cancer is a blood cancer, or a solid tumor. In some variations, 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. In other variations of the aspects described herein, the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome. In certain variations of the aspects described herein, the disorder is associated with a mutation of K- Ras.
DESCRIPTION OF THE FIGURES
[0028] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.
[0029] 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.
[0030] 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). “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.
[0031] FIG. 3 depicts confocal images of the effect of compound 1-0175 on cell membrane localization of K-Ras4b in HeLa cells.
[0032] 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.
[0033] FIGS. 5A-5D depicts results from cell proliferation assays with selected compounds in MEF cells after 72 h incubation, (ICso values, mM).
[0034] FIG. 6 is a table listing the ICso ratio of selected compounds in G12D vs. Myr- G12D MEFs.
[0035] 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
G12D/C185 MEFs) for selected compounds.
[0036] 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. In FIG. 8A, 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. In FIG. 8C, bracketed compounds demonstrated higher activity in MEFs expressing KRAS4b G12V , compared to KRAS4a, HRAS, or Myr-KRAS G12D/C185S cells.
[0037] 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.
[0038] FIG. 10 is a table summarizing the data displayed in FIG. 9.
DETAILED DESCRIPTION
[0039] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.
[0040] Provided herein is 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. In some embodiments, 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. For example, in some embodiments, this compound may block the farnesylation of the newly synthesized K-Ras, preventing its C-terminal processing. In other embodiments, 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. In some embodiments, 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. In some embodiments, 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. These compounds, compositions comprising said compounds, and methods of using said compounds and compositions are described in greater detail below.
I. Compounds of Formula (X)
[0041] In some aspects, provided herein is a compound of Formula (X):
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rxl, Rx2, and Rx3 are independently hydrogen, -CN, or alkyl; or Rx2 and Rx3 together form alkenyl; or Rxl and Rx2 together with the carbon atoms to which they are attached form heterocycloalkenyl or cycloalkenyl; or Ral and Rx2 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 -ORx4, wherein each Rx4 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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N02, -CN, -S02NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein when A is phenyl, Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, cycloalkyl,
heterocycloalkyl, -N02, -CN, -S02NH2, -NRa7Ra8, -ORa9, and -S02Ral°; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently
unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N02, -CN, -S02NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, 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)-, Ral and one Ra4, together with the atoms to which they are attached, form a spirocycle with ring A, wherein the spirocycle is
unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein 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,
-ORa16, =0,
-NRal7Ral8,-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each
Figure imgf000022_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, Ra35, Ra54, and Ra55, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra2\ -ORa24, and
-SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, and Ra39 is independently hydrogen, alkyl, or haloalkyl; wherein each alkyl or haloalkyl or Ra22 and Ra23 is independently
unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which 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 Ra40 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.
[0042] "Alkyl", as used herein, refers to an unbranched or branched saturated hydrocarbon chain. In some embodiments, 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-C4)alkyl). Examples of 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. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed. Thus, for example, "butyl" can include n-butyl, sec-butyl, isobutyl and t-butyl, and "propyl" can include n-propyl and isopropyl.
[0043] “Haloalkyl”, as used herein, refers to an alkyl group substituted with one or more halo, which may be selected independently. Thus, 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, -CH2Br, and -CH2CHFCH2CH2Br.
[0044] “Alkenyl”, as used herein, refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon double bond. In some embodiments, 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- C4)alkenyl). Alkenyl may have one, two, three, four, five, or more carbon-carbon double bonds, as valency permits. When an alkenyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
[0045] “Cycloalkenyl”, as used herein, refers to a non-aromatic monocyclic or polycyclic hydrocarbon comprising one or more carbon-carbon double bonds. In some embodiments, cycloalkenyl has 3 to 50 carbon atoms ((C3-Cso)cycloalkenyl), 3 to 20 carbon atoms ((C3- C2o)cycloalkenyl), 3 to 12 carbon atoms ((C3-Ci2)cycloalkenyl), 3 to 8 carbon atoms ((C3- C8)cycloalkenyl), 3 to 6 carbon atoms ((C3-C6)cycloalkenyl), or 3 to 5 carbon atoms ((C3- C4)cydoalkenyl).
[0046] “Alkynyl”, as used herein, refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon triple bond. In some embodiments, 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- C4)alkynyl). Alkynyl may have one, two, three, four, five, or more carbon-carbon triple bonds, as valency permits. When an alkynyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
[0047] “Cycloalkyl”, as used herein, refers to a monocyclic or polycyclic saturated hydrocarbon. In some embodiments, cycloalkyl has 3 to 50 carbon atoms ((C3- C5o)cycloalkyl), 3 to 20 carbon atoms ((C3-C2o)cycloalkyl), 3 to 12 carbon atoms ((C3- Ci2)cycloalkyl), 3 to 8 carbon atoms ((C3-C8)cycloalkyl), 3 to 6 carbon atoms ((C3- C6)cycloalkyl), or 3 to 5 carbon atoms ((C3-C4)cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro- liT-indene, decahydronaphthalene, cubane, bicyclo[3.l.0]hexane, and bicyclo[ 1.1.1 ]pentane.
[0048] “Halocycloalkyl”, as used herein, refers to a cycloalkyl group substituted with one or more halo, which may be selected independently. Thus, 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.
[0049] "Aryl", as used herein, 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). In certain embodiments, 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. For example, in some embodiments, 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). In some embodiments, aryl as used herein has from 6 to 14 carbon atoms ((C6- Ci4)aryl), or 6 to 10 carbon atoms ((C6-Cio)aryl). Where the aryl includes fused rings, the aryl may connect to one or more substituents or moieties of the formulae described herein through any atom for which valency permits. In some embodiments, aryl comprises one ring, two fused rings, three fused rings, four fused rings, or more.
[0050] "Heteroaryl", as used herein, refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S. The heteroaryl group may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g., be a 5-membered, 6-membered, 7- membered, 8-membered, 9-membered, lO-membered, l l-membered, or l2-membered heteroaryl). In some embodiments, 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). In certain embodiments, 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). In some embodiments, 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). In still further
embodiments, heteroaryl includes polycyclic groups with two fused aromatic rings, wherein each ring comprises at least one ring heteroatom (e.g, naphthyridinyl). In some
embodiments, 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. In some embodiments, heteroaryl comprises greater than 5 ring heteroatoms. In one example, a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S.
Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl. In some embodiments, a heteroaryl substituted with =0 is still a heteroaryl.
[0051] “Heterocycloalkyl”, as used herein, 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). In some embodiments, 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. In one example, a heterocycloalkyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycloalkyl comprises one ring, two rings, three rings, four rings, or more, for example as a polycyclic fused system. In some embodiments, heterocycloalkyl comprising multiple rings includes spirocyclic systems in which one or more rings comprise one or more heteratoms. Examples of 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. [0052] “Halo” or“halogen” includes bromo, chloro, fluoro, and iodo.
[0053] The term“substituted” as used herein 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.
[0054] It should be understood that when a range of values is listed, it is intended to encompass each value and sub-range within the range. For example,“(Ci-C6)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, C4, 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, C4-6, C4-5, and C5-6 alkyl.
[0055] In some embodiments of the compound of Formula (X), A is heteroaryl, cycloalkyl, or heterocycloalkyl. In some embodiments, 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. In certain embodiments, 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. In other embodiments, A is
9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms
independently selected from the group consisting of O, N, and S.
[0056] In some embodiments of the compound of Formula (X), or a pharmaceutically acceptable salt thereof, A is heterocycloalkyl. For example, in some embodiments, A is 3- to
10-membered heterocycloalkyl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, 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. In certain embodiments, A is a 5,5-ring fused
heterocycloalkyl, 6,6-ring fused heterocycloalkyl, or 5,6-ring fused heterocycloalkyl. In some embodiments of the compound of Formula (X), or a pharmaceutically acceptable salt thereof, A is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or tropanyl.
[0057] In other embodiments of the compound of Formula (X), or a pharmaceutically acceptable salt thereof, A is heteroaryl. For example, in some embodiments, A is 5- to 10- membered heteroaryl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, A is 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, A 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, 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. In some embodiments of the compound of Formula (X), or a pharmaceutically acceptable salt thereof, 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.
[0058] In other embodiments of the compound of Formula (X), or a pharmaceutically acceptable salt thereof, A is aryl. For example, in some embodiments, A is (C6-Cio)aryl, such as C6-aryl, (C7-Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl. In certain embodiments of the compound of Formula (I), Formula (I-A), or Formula (I-B), or a pharmaceutically acceptable salt thereof, A is phenyl or naphthyl. In some embodiments, 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.
[0059] In still further embodiments of the compound of Formula (X), or a pharmaceutically acceptable salt thereof, A is cycloalkyl. For example, in some embodiments, A is (C3- Cio)cycloalkyl. In certain embodiments, A is (C5-Cio)cycloalkyl. In other embodiments, A is (C5-C7)cycloalkyl. In still other embodiments, A is (C8-Cio)cycloalkyl. In some
embodiments, A is C3-cycloalkyl, C4-cycloalkyl, Cs-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or Cio-cycloalkyl. In some embodiments, A is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl. In some embodiments of the compound of Formula (X), or a pharmaceutically acceptable salt thereof, A is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tri cyclooctyl.
[0060] In some embodiments, the compound of Formula (X) is a compound of Formula (X-
I):
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof, wherein A is 4- to lO-membered heterocycloalkyl, and B, X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, Ra5, m, and n are as defined for
Formula (X).
[0061] In some embodiments of the compound of Formula (X-I), or a pharmaceutically
acceptable salt thereof,
Figure imgf000030_0002
integer from 0 to 12. In other embodiments,
Figure imgf000031_0001
Figure imgf000031_0002
integer from 0 to 12.
[0062] In some embodiments, the compound of Formula (X) or Formula (X-I) is a compound of Formula (X-A):
Figure imgf000031_0003
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (X).
[0063] In some embodiments, the compound of Formula (X) or Formula (X-I) is a compound of Formula (X-C):
Figure imgf000031_0004
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, R52, Rx3, Ral, R32, Ra3, Ra4, Ra5, and n are as defined for Formula (X).
[0064] In some embodiments, the compound of Formula (X) or Formula (X-I) is a compound of Formula (X-B):
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2- -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6 ‘)2— , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
r is 0, 1, or 2;
p is an integer from 0 to 7;
Figure imgf000032_0002
are as defined for Formula
(X).
[0065] In some embodiments, the compound of Formula (X) is a compound of Formula (X- A-i):
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X).
[0066] In some embodiments, the compound of Formula (X) is a compound of Formula (X- C-i):
Figure imgf000033_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X). [0067] In some embodiments of the compound of Formula (X-A) or (X-A-i), or a
pharmaceutically acceptable salt thereof,
Figure imgf000034_0001
and p is an integer from 0 to 6. In other embodiments,
Figure imgf000034_0002
Figure imgf000034_0003
integer from 0 to 6. In some embodiments of the compound of Formula (X-C) or (X-C-i), or a pharmaceutically acceptable salt thereof,
Figure imgf000034_0004
integer from 0 to 6. In
other embodiments,
Figure imgf000034_0005
integer from 0 to 6.
[0068] In certain embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (X-A-i), or Formula (X-C-i), or a pharmaceutically acceptable salt thereof, one of Rxl, R52, and Rx3 is unsubstituted or substituted alkyl. In some embodiments, two of Rxl, Rx2, and Rx3 is unsubstituted or substituted alkyl. In still further embodiments, three of Rxl, Rx2, and Rx3 is unsubstituted or substituted alkyl. In some embodiments, the alkyl is (Ci-C4)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-C4)alkyl, and -0-(Ci- C4)haloalkyl.
R x2 RX2 R: x2
[0069] In some embodiments,
Figure imgf000035_0001
In certain
embodiments,
Figure imgf000035_0002
[0070] In some embodiments, one of Rxl, Rx2, and Rx3 is -CN.
[0071] In still further embodiments, Rx2 and Rx3 together form alkenyl. For example, in some embodiments, R52 and Rx3 together with the carbon to which they are attached form a (C2-Cio)alkenyl. In some embodiments, R52 and Rx3 together with the carbon to which they are attached form a C2-alkenyl. In some embodiments, the alkenyl is substituted with one or more substituents independently selected from the group consisting of halo and -ORx4, wherein each Rx4 is independently H, alkyl, or haloalkyl. Thus, for example, in some embodiments the alkenyl 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. In some embodiments, each halo is independently chloro or fluoro. In some embodiments, the alkenyl is unsubstituted.
RX2
[0072] In some embodiments,
Figure imgf000035_0003
. In certain embodiments, Rxl is hydrogen. [0073] In some embodiments, Rxl and Rx2 together with the carbon atoms to which they are attached form heterocycloalkenyl, or cycloalkenyl. In some embodiments, the heterocycloalkenyl is a 5- to lO-membered heterocycloalkenyl, or a 5- to 8-membered heterocycloalkenyl. In some embodiments, the cycloalkenyl is a (C4-Cio)cycloalkenyl, or a (C5-C8)cycloalkenyl, or a (C5-C6)cycloalkenyl. In some embodiments, the
heterocycloalkenyl or cycloalkenyl is unsubstituted. In other embodiments, the
heterocycloalkenyl or cycloalkenyl is substituted with one or more substituents independently selected from the group consisting of halo and -ORx4, wherein each Rx4 is independently H, alkyl, or haloalkyl. Thus, for example, in some embodiments 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. In some
embodiments, each halo is independently chloro or fluoro.
[0074] Thus, for example, in some embodiments,
Figure imgf000036_0001
Figure imgf000036_0002
[0075] In certain embodiments, Ral and Rx2 together with the atoms to which they are attached form heterocycloalkenyl. In some embodiments, 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. In some embodiments, the heterocycloalkenyl comprises one double bond. In certain embodiments, the
heterocycloalkyl is substituted with one or more substituents independently selected from the group consisting of halo and -ORx4, wherein each Rx4 is independently H, alkyl, or haloalkyl. Thus, for example, in some embodiments 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. In some embodiments, each halo is independently chloro or fluoro. In other embodiments, the heterocycloalkenyl is unsubstituted. In some embodiments, Ral and Rx2 together with the atoms to which they are attached form an
unsubstituted heterocycloalkenyl. Thus, for example, in some embodiments,
Figure imgf000037_0001
Figure imgf000037_0002
[0076] In certain embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (X-A-i), or Formula (X-C-i), or a pharmaceutically acceptable salt thereof, such as other embodiments described herein, one of Rxl, Rx2, and Rx3 is hydrogen. In some embodiments, Rxl is hydrogen. In some
embodiments, Rx2 is hydrogen. In other embodiments, Rx3 is hydrogen. In certain embodiments, both Rx2 and Rx3 are hydrogen. In still further embodiments, Rxl and Rx2 are hydrogen. In other embodiments, both Rxl and Rx3 are hydrogen. In certain embodiments, each of Rxl, Rx2, and Rx3 are hydrogen.
[0077] In some embodiments, the compound of Formula (X) is a compound of Formula (I):
Figure imgf000037_0003
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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -SCkR310, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -NH2,
-NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SO3H, -SCNH, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)-alkyl, -NHC(0)0- alkyl, -NHC(0)0H, -NHOH, -OH, -O-alkyl, -O-haloalkyl, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo,
-ORa16, =0, -NRal7Ra18,
-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each
Figure imgf000039_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra2\ -ORa24, and
-SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13; and
n is an integer from 0 to 11.
[0078] In some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (X-A-i), Formula (X-C-i), Formula (I), or a pharmaceutically acceptable salt thereof, each Ra4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN,
-SO2NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -NIL·, -CCh, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHL·, -OH, -COOH, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHC(0)-alkyl, -NHC(0)0-alkyl, -NHOH, -OCCh, -OCBn, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -CONH2, -NO2, -NH(alkyl), -C(0)0-alkyl, -O-alkyl, alkyl (such as (Ci-C8)alkyl, (Ci-Ce)alkyl, or (Ci-C4)alkyl), cycloalkyl (such as (C3-C8)cycloalkyl, (C3-C6)cycloalkyl, or (Cs-C6)cydoalkyl),
heterocycloalkyl (such as 3- to 8-membered heterocycloalkyl, 3- to 6-membered
heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (such as (C6-Cio)aryl,
(Cio)aryl, or phenyl), and heteroaryl (such as 5- to lO-membered heteroaryl, 5- to 9- membered heteroaryl, or 5- to 6-membered heteroaryl).
[0079] In some embodiments of the compound of Formula (I):
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -SCkR310, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2,
-NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52,
-SOzRa53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each
Figure imgf000043_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra23, -ORa24, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; and n is an integer from 0 to 11.
[0080] In some embodiments of the compound of Formula (I):
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, or cycloalkyl, wherein when Ral is alkyl, X is -S(O)-, -S(0)2- , -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -SCkR310, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, or halocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or Ra2 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ra3 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -SCkR353, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocylaolkyl, aryl, or heteroaryl; each aryl, heteroaryl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -SFs, and Ra35, wherein Ra35 is independently alkyl, cycloalkyl, heterocylaolkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-SOzRa57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each
Figure imgf000046_0001
Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each Ral1, Ral2, Ral9, Ra20, and Ra21 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; each Ral3 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral9, Ra20, Ra21, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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,
-NRa22Ra2\ -ORa24, and -SFs; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; and n is an integer from 0 to 11.
[0081] In certain embodiments of the compound of Formula (X), Formula (X-I), or Formula (I), or a pharmaceutically acceptable salt thereof, 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. In certain embodiments, A is a 5- or 6-membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. For example, in some embodiments A is pyrrolidinyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, thiomorpholinyl, morpholinyl, or piperazinyl. In some embodiments, A is piperidinyl. In other embodiments, A is pyrrolidinyl. In some embodiments, A is a 4-membered heterocycloalkyl.
[0082] In some embodiments of the compound of Formula (I), or a pharmaceutically
acceptable salt thereof,
Figure imgf000047_0001
integer
from 0 to 12. In other embodiments,
Figure imgf000047_0002
an integer from 0 to 12.
[0083] In some embodiments, the compound of Formula (I) is a compound of Formula (I-
A):
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (I).
[0084] In some embodiments, the compound of Formula (I) is a compound of Formula (I- C):
Figure imgf000048_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (I).
[0085] In some embodiments of the compound of Formula (X-A), Formula (X-A-i), Formula (X-C), Formula (X-C-i), Formula (I-A), or Formula (I-C), or a pharmaceutically acceptable salt thereof, 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.
[0086] In other embodiments, the compound of Formula (I) is a compound of Formula (I-
B):
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2- -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2- wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
r is 0, 1, or 2;
p is an integer from 0 to 7;
and B, Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (I).
[0087] In certain embodiments of the compound of Formula (X-B) or Formula (I-B), or a pharmaceutically acceptable salt thereof, Y is -C(Ra45)2-, wherein each Ra45 is independently hydrogen or Ra4. In certain embodiments, Y is -CFh- In other embodiments, Y is -CHRa4-. In some embodiments, Y is -C(Ra4)2- In other embodiments, Y is -S(0)r-, where r is 0, 1, or 2. For example, in some embodiments, Y is -S-. In other embodiments, Y is -S(O)-. In still further embodiments, Y is -S(0)2- In some embodiments, Y is -0-. In other embodiments, Y is -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4. For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NRa4-.
[0088] In some embodiments of the compound of Formula (X-B) or Formula (I-B), or a pharmaceutically acceptable salt thereof, 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. [0089] In some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is heteroaryl, cycloalkyl, or heterocycloalkyl. In some embodiments, 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. In certain embodiments, 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. In other embodiments, 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.
[0090] In some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is heterocycloalkyl. For example, in some embodiments, B is 3- to lO-membered heterocycloalkyl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, B is 5- to lO-membered heterocycloalkyl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, 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. In some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or tropanyl. In certain embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is:
Figure imgf000051_0001
[0091] In other embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is heteroaryl. For example, in some embodiments, B is 5- to lO-membered heteroaryl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, B is 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, B is 9- or lO-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 9- or 10- membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl. In some
embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X- B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, 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,
quinoxalinyl, quinolyl, naphthyridinyl, or pyrrolyl. In certain embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is:
Figure imgf000052_0001
[0092] In other embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is aryl. For example, in some embodiments, B is (C6-Cio)aryl, such as C6-aryl, (C7-Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl. In certain embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is phenyl or naphthyl. In some embodiments, 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. In certain embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is:
Figure imgf000053_0001
[0093] In still further embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is cycloalkyl. For example, in some embodiments, B is (C3-Cio)cycloalkyl. In certain embodiments, B is (Cs- Cio)cycloalkyl. In other embodiments, B is (C5-C7)cycloalkyl. In still other embodiments, B is (C8-Cio)cycloalkyl. In some embodiments, B is C3-cycloalkyl, C4-cycloalkyl, Cs- cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or Cio-cycloalkyl. In some embodiments, B is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl. In some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tri cyclooctyl. In certain embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is:
Figure imgf000053_0002
[0094] It should be understood in embodiments described herein, B may be unsubstituted or substituted with one to eleven Ra5 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.
[0095] For example, in some embodiments, B is \ ( B )— (Ra5)n (Ra5)n-T
===/ , as described above, and is ==/ , wherein n is an integer from 0 to 5.
[0096] In other embodiments, B is
Figure imgf000054_0002
, as described above, and
Figure imgf000054_0001
is
Figure imgf000054_0003
, wherein n is an integer from 0 to 11.
[0097] In still other embodiments B is
Figure imgf000054_0005
as described above, and
Figure imgf000054_0004
is
(Ra5)n^NH
1- wherein n is an integer from 0 to 10. For example in some embodiments,
Ra5
Figure imgf000054_0006
. When multiple instances of a substituent (for example, Ra ) are present, it should be understood that they may be optionally different unless otherwise indicated.
[0098] In some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, 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.
[0099] In some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, B is phenyl, and n is an integer from 0 to 5. Thus, for example, in some embodiments of the compound of Formula (X), Formula (X-I), Formula (X-A), Formula (X-B), Formula (X-C), Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof,
Figure imgf000055_0001
Figure imgf000055_0002
. When multiple instances of a substituent (for example, Ra5) are present, it should be understood that they may be optionally different unless otherwise indicated.
[0100] In certain variations, the compound of Formula (I) is a compound of Formula (I-A- i):
Figure imgf000055_0003
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and X, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined for Formula (I). [0101] In some embodiments, the compound of Formula (I) is a compound of Formula (I-
C-i):
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and X, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined for Formula (I).
[0102] In some embodiments of the compound of Formula (I-A-i) or Formula (I-C-i), or a pharmaceutically acceptable salt thereof, 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.
[0103] In some embodiments of the compound of Formula (I-A) or Formula (I-A-i), or a
Figure imgf000056_0002
and p is an integer from 0 to 6. In some embodiments of the compound of Formula (I-C) or
Figure imgf000057_0002
from 0 to 6.
[0104] In other variations, the compound of Formula (I) is a compound of Formula (I-B-i):
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-,— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when Y is -CH2-, X is -S(O)-, -S(0)2- -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; r is 0, 1, or 2; p is an integer from 0 to 7; and Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (I).
[0105] In certain embodiments of the compound of Formula (I-B-i), or a pharmaceutically acceptable salt thereof, Y is -C(Ra45)2-, wherein each Ra45 is independently hydrogen or Ra4. In certain embodiments, Y is -CFh- In other embodiments, Y is -CHRa4-. In some embodiments, Y is -C(Ra4)2- In other embodiments, Y is -S(0)r-, wherein r is 0, 1, or 2. For example, in some embodiments, Y is -S-. In other embodiments, Y is -S(O)-. In still further embodiments, Y is -S(0)2- In some embodiments, Y is -0-. In other embodiments, Y is -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4. For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NRa4-.
[0106] In some embodiments of the compound of Formula (I-B-i) or a pharmaceutically acceptable salt thereof, 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.
[0107] In some embodiments of the compound of Formula (I-B) or Formula (I-B-i), or a
pharmaceutically acceptable salt thereof,
Figure imgf000058_0001
p is an integer from 0 to 6. In other embodiments,
Figure imgf000058_0002
Figure imgf000058_0003
and p is an integer from 0 to 6.
[0108] In some embodiments of 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, each Ra5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, - NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15. In some embodiments, one or more Ra5 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;
heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3-C6)cycloalkyl unsubstituted or substituted with one or more fluoro or chloro; and (Ci-Ce)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C6)cycloalkyl, 3- to 6- membered heterocycloalkyl, aryl, heteroaryl, halo, -OH, -0-(Ci-C4)alkyl, =0, -NRa20Ra2 1, and -CN. In certain embodiments, one or more Ra5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In certain embodiments, each Ra5 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. In some embodiments, one or more Ra5 is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2,
-CH2F, -CHF2, -CFs, -OCH2F, -OCHF2, -OCF3, -NO2, phenyl, =0, -SO2NH2, cyclopropyl, and cyclohexyl. In some embodiments, at least one Ra5 is halo, -0-(Ci-C6)alkyl,
-0-(Ci-C6)haloalkyl, or -CN. In certain embodiments, at least one Ra5 is chloro, fluoro, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F, -CHF2, -CFs, -OCH2F, -OCHF2, -OCFs, or -CN. In certain embodiments, at least one Ra5 is chloro, fluoro, -OCH3, or -CN. In some embodiments, each Ra5 is independently chloro, fluoro, -OCH3, or -CN. In some
embodiments, at least one Ra5 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F, -CHF2, -CFs, -CH2CI, -CHCI2, -CCI3, -CH2Br, -CHBr2, -CBrs, -CH2I, -CHFI2, -CIs, -OCH2CI, -OCHCI2, -OCCI3, -OCH2Br, -OCHBn, -OCBrs, -OCH2I, -OCHFI2, -OCI3, -OCH2F, -OCHF2, -OCFs, -NO2, phenyl, =0, -SO2NH2, -CN, cyclopropyl, cyclohexyl, and -OCH2CCH.
[0109] In some embodiments of 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, at least one Ra5 is alkyl, wherein each alky is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SF5, -S02NRa54Ra55, -SRa56, -S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Ra58 is independently (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8- membered heteroaryl. In some embodiments, the alkyl is unbranched. In other embodiments, the alkyl is branched. In some embodiments, at least one Ra5 is alkyl, wherein the alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halocycloalkyl,
heterocycloalkyl, aryl, heteroaryl, halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56, and -SCkR357. In some embodiments, 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. In other embodiments, 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-C4)alkyl, wherein the alkyl is unsubstituted or substituted as described herein. In some embodiments, at least one Ra5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, difluoromethyl, or fluoromethyl.
[0110] In some embodiments of 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, at least one Ra5 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -SCkR353, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, each Ra35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl.
[0111] In some embodiments, Ra35 is unsubstituted alkyl. In some embodiments, Ra35 is unsubstituted (Ci-C6)alkyl. In other embodiments, Ra35 is alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkynyl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -ORa24, and -SFs. In certain embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkynyl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -OR324, and -SFs. In some embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -SFs, -OH, -O- (Ci-Ce)alkyl, and -0-(Ci-C6)haloalkyl. In certain embodiments, Ra35 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
[0112] In some embodiments of 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, at least one Ra5 is branched alkyl. In some embodiments, the branched alkyl is (C3-C5) branched alkyl. In some embodiments, the branched alkyl is isopropyl. In some embodiments, the branched alkyl is substituted with two or more substituents independently selected from the group consisting of =0, -NRa20Ra2 1, -ORa19, and Ra58. In some embodiments, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkynyl, -CN, =0, -OR324, and -NRa22Ra23, wherein each alkyl is independently unsubstituted or substituted with one or more halo. In some embodiments, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, alkyl, haloalkyl, alkynyl, -CN, and =0. In some embodiments, wherein Ra5 is branched alkyl substituted with one or more -NRa20Ra21, each Ra20 and Ra21 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. In some embodiments, wherein one or both of R320 and R321 are independently alkyl, each alkyl is independently unsubstituted substituted with one or more substituents independently selected from the group consisting of halo, =0, -NRa22Ra23, -OR324, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, 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, haloalkyl, -NRa36Ra37, and -OR340. In some embodiments, at least one of R320 and R321 is not hydrogen. In certain embodiments, both R320 and R321 are not hydrogen.
[0113] In some embodiments, at least one R35 is isopropyl, wherein one terminal methyl of the isopropyl is substituted with phenyl. In some embodiments, the phenyl is unsubstituted. In other embodiments, the phenyl is substituted with one to three substituents independently selected from the group consisting of halo, haloalkyl, -NRa22Ra23, and -ORa24. In some embodiments, Ra22, Ra23, and Ra24 are independently hydrogen, (Ci-C4)alkyl, or (Ci- C4)haloalkyl. In some embodiments, one terminal methyl of the Ra5 isopropyl is substituted with =0 and -NRa20Ra21 or =0 and Ra58. In some embodiments, Ra58 is heterocycloalkyl. In some embodiments, the heterocycloalkyl is unsubstituted. In other embodiments, the heterocycloalkyl is substituted.
[0114] In some embodiments of 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, at least one Ra5 is -NRallRa12. In some embodiments, at least one of Ral1 and Ral2 is not hydrogen. In certain embodiments, both of Ral1 and Ral2 are not hydrogen. In certain embodiments, at least one of Ral1 and Ral2 is substituted alkyl. In certain embodiments, both of Ral1 and Ral2 are substituted alkyl. For example, in some embodiments, Ral1 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted. In some embodiments, the aryl or heteroaryl is unsubstituted. In other embodiments, the aryl or heteroaryl is substituted with one or more substituents selected from the group consisting of halo, haloalkyl, -SFs, -NRa36Ra37, and - ORa40. In some embodiments, Ral2 is alkyl substituted with one or more substituents independently selected from the group consisting of =0, -NRa22Ra23, -OR324, and
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, -NRa36Ra37, and -ORa40. In some embodiments, when Ral1 or Ral2 is alkyl, or both Ral1 and Ral2 are alkyl, each alkyl is independently (Ci- C4)alkyl.
[0115] In some embodiments of 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, at least one Ra5 is -NRallRa12, wherein Ral1 is Ci-alkyl substituted with aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and Ral2 is hydrogen or alkyl. In some embodiments, where Ral2 is alkyl, the alkyl of Ral2 is substituted with one or more substituents independently selected from the group consisting of =0, aryl, heteroaryl, -NRa22Ra23, and -ORa24. In certain embodiments, each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (e.g., substituting the Ci-alkyl of Ral1 or alkyl of Ral2) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -SFs, -NRa36Ra37, and -ORa40. In some embodiments, 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.
[0116] In some embodiments of 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, at least one Ra5 is alkyl substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, and Ra58, wherein Ra58 is heterocycloalkyl. In some embodiments, at least one Ra5 is alkyl substituted with one or more substituents independently selected from the group consisting of =0, -NRa20Ra2 1, and Ra58, wherein Ra58 is heterocycloalkyl. In certain embodiments, at least one of Ra20 and Ra21 is not hydrogen. In some embodiments, the alkyl is (Ci-C4)alkyl. In certain embodiments, the alkyl is (Ci-C2)alkyl. In certain embodiments, at least one Ra5 is Ci-alkyl substituted with -NRa20Ra21, wherein at least one of Ra20 and Ra21 is not hydrogen. In some embodiments, at least one Ra5 is C2-alkyl substituted with =0 and - NRa20Ra21, wherein at least one of Ra20 and Ra21 is not hydrogen.
[0117] In still further embodiments of 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, one or more Ra5 is a substituted alkyl of formula (a):
Figure imgf000063_0001
wherein: w is 0 or 1; Ra20 and Ra21 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
independently selected from the group consisting of halo, =0, -NRa22Ra23, -ORa24, 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.
[0118] In some embodiments of 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, at least one Ra5 is alkenyl, wherein each alkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SF5, -SO2NRa50Ra51, -SRa52, -SCkR353, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Ra35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Ra5 is alkenyl, wherein the alkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, and -SCkR353. In some embodiments, at least one Ra5 is alkenyl, wherein each alkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3- C6)cycloalkyl, (C6-Cio)aryl, 3- to 6-membered heteroaryl, halo, -OH, -OH-(Ci-Ce)alkyl, =0, — NRal7Ra18, -CN, and -SFs. In some embodiments, at least one Ra5 is unsubstituted alkenyl. In some embodiments, 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. In some embodiments, the alkenyl is a branched (C2-C6)alkenyl substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -ORa16, =0, and -NRal7Ra18. In some embodiments, 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.
[0119] In some embodiments of 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, at least one Ra5 is cycloalkyl, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SF5, -SO2NRa50Ra51, -SRa52, -SCkR353, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Ra35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Ra5 is cycloalkyl, wherein the cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, and -SCkR353. In some embodiments, at least one Ra5 is cycloalkyl, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, (C6-Cio)aryl, 3- to 6-membered heteroaryl, halo, -OH, -OH- (Ci-Ce)alkyl, =0, -NRal7Ra18, -CN, and -SFs. In some embodiments, at least one Ra5 is unsubstituted cycloalkyl.
[0120] In some embodiments of 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, at least one Ra5 is aryl, wherein each aryl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Ra35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Ra5 is aryl, wherein the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -SFs, and Ra35. In some embodiments, Ra35 is unsubstituted (Ci-C6)alkyl. In other embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -OR324, and -SFs. In some embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents
independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci- C6)haloalkyl. In some embodiments, at least one Ra5 is unsubstituted aryl.
[0121] In certain embodiments of 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 stereoisomer or pharmaceutically acceptable salt thereof, at least one Ra5 is heteroaryl, wherein each heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Ra35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered
heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Ra5 is heteroaryl, wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -SFs, and Ra35. In some embodiments, Ra35 is unsubstituted (Ci-C6)alkyl. In other embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -ORa24, and -SFs. In some embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In some embodiments, at least one Ra5 is unsubstituted heteroaryl. [0122] In certain embodiments of 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 stereoisomer or pharmaceutically acceptable salt thereof, at least one Ra5 is heterocycloalkyl, wherein each heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Ra35 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Ra5 is heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -SFs, and Ra35. In some embodiments, Ra35 is unsubstituted (Ci-C6)alkyl. In other embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -ORa24, and -SFs. In some embodiments, Ra35 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In some embodiments, at least one Ra5 is unsubstituted heterocycloalkyl.
[0123] In some embodiments of 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, each Ral1, Ral2, Ral3, Ral4, Ral5, Ral6,
Figure imgf000067_0001
independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl. In certain embodiments, each Ral1, Ral2, Ral3, Ral4, Ral5,
Ra16 p^al7 ^a I X ^a I 9 p^a20 ^a21 p^a4X j^a49 p^aSO ^aS I p^aS2 j^a53 p^aS4 ^aSS ^a56 ^^p Ra57 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C3- C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, (C6-Cio)aryl, 3- to lO-membered heteroaryl, (C2-C6)alkynyl, or (C2-C6)haloalkynyl. [0124] In some embodiments of 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, each Ral4, Ral5, Ral6, Ral7, Ral8, Ra48, Ra49, Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In some embodiments, each Ral4, Ral5, Ral6, Ral7, Rai8, Ra48, Ra49, Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, and (C3- C6)halocycloalkyl. In certain embodiments, each Ral 1, Ral2, Ral9, R320, and Ra21 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl. In certain embodiments, each Ral 1, Ral2, Ral9, Ra20, and R321 is independently hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to lO-membered heterocycloalkyl, 3- to lO-membered heteroaryl, or (C6-Cio)aryl. In some embodiments, each Ral3 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl. In certain embodiments, each Ral3 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.
[0125] In some embodiments of 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, each alkyl, cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl of Ral 1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, Ra21, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra23, -OR324, and -SFs; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -OR340, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl.
[0126] In certain embodiments, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, (C6-Cio)aryl, 5- to lO-membered heteroaryl, (Ci-Ce)alkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl, 5- to lO-membered heterocycloalkyl, -NRa22Ra23, -ORa24, and -SFs; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently (C3-C6)cycloalkyl, 5- to 10- membered heterocycloalkyl, (C6-Cio)aryl, or 5- to lO-membered heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -ML·, -SFs, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl.
[0127] In certain embodiments, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral9, R320, Ra21, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 is independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NRa22Ra23, -OR324, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo,
-CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -OR340, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NH2, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl.
[0128] In certain embodiments, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral9, R320, Ra21, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 is independently selected from the group consisting of halo, =0, -CN, (C6-Cio)aryl, 5- to lO-membered heteroaryl, (Ci-Ce)alkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl, 5- to lO-membered heterocycloalkyl, -NRa22Ra23, -ORa24, and -SFs; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently (C3-C6)cycloalkyl, 5- to 10- membered heterocycloalkyl, (C6-Cio)aryl, or 5- to lO-membered heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NH2, -SFS, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl.
[0129] In some embodiments, each R322, Ra23, R324, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl. In certain embodiments, each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl.
[0130] In certain variations of 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, at least one of Ra5 is:
Figure imgf000070_0001
wherein: Ra25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORa28, -SFs, and
-NRa29Ra30; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -SFs, =0, -ORa31,
-NRa41Ra42, -NRa43C(0)Ra44, cycloalkyl, and heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, halo, -OH, and -SFs; each Ra26 and Ra27 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, -ORa32, and
-NRa33Ra34; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =0, and -SFs; or one Ra26 and one R327 attached to the same atom, 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 Ra2X, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra41, Ra42, Ra43, and Ra44 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2. [0131] In some embodiments, each Ra2X, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra41, Ra42, Ra43, and Ra44 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl. In some
embodiments, each Ra28, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra41, Ra42, Ra43, and Ra44 is independently hydrogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, or halobutyl.
[0132] In some embodiments, Ra25 is hydrogen. In other embodiments, Ra25 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -OR328, -SFs, and -NRa29Ra30. In still other embodiments, Ra25 is aryl, wherein the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -OR328, -SFs, and -NRa29Ra30.
[0133] In certain embodiments, Ra25 is alkyl, wherein the alkyl is unsubstituted or substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is independently
unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkynyl, alkyl, haloalkyl, halo, -SFs, =0, -OR331, -NRa41Ra42,
-NRa43C(0)Ra44, and heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =0. In some embodiments, the aryl or heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C2-C6)alkynyl, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, halo, -SFs, =0, -OH, -0(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -NHC(0)H, -NHC(0)-(Ci-C6)alkyl, -NH2, -NH(Ci- C6)alkyl, and 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is
unsubstituted or substituted with =0.
[0134] In some embodiments, Ra25 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -SFs, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C6-Cio)aryl, and 3- to 6-membered heteroaryl; wherein the aryl and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (Ci-C6)haloalkyl, (Ci-C6)alkyl, -SFs, -OH, -0(Ci-C6)alkyl, =0, -NRa41Ra42, and -NRa43C(0)Ra44. In some embodiments, Ra25 is alkyl substituted with one or more (C6-Cio)aryl, wherein each aryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -OH, -0(Ci-C6)alkyl, -SF5, -NHC(0)-(Ci-C6)alkyl, and 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =0. In certain embodiments, Ra25 is (Ci- C6)alkyl, wherein the alkyl is unsubstituted or substituted with one or more (C6-Cio)aryl or 3- to 6-membered heteroaryl.
[0135] In certain embodiments, Ra25 is unsubstituted (Ci-C6)alkyl. In other embodiments, Ra25 is (Ci-Ce)alkyl substituted with 3- to 6-membered heteroaryl. In other embodiments, Ra25 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-C6)alkynyl, (Ci-C6)haloalkyl, -OH, -0(Ci-C6)alkyl, -SFs, -NHC(0)H, and -NHC(O)- (Ci-C6)alkyl. In other embodiments, Ra25 is (Ci-Ce)alkyl substituted with phenyl, wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -OH, -0(Ci-C6)alkyl, -SFs, -NHC(0)H, -NHC(0)-(Ci-C6)alkyl, =0, -NH2, and -NH(Ci-C6)alkyl.
[0136] In some embodiments, Ra25 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. In other embodiments, Ra25 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.
[0137] In some embodiments, Ra25 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
heterocycloalkyl is unsubstituted or substituted with =0. In other embodiments, Ra25 is (C3- C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C6)alkyl.
[0138] In some embodiments, Ra25 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, (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 heterocycloalkyl is unsubstituted or substituted with =0. In other embodiments, Ra25 is 3- to lO-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C6)alkyl.
[0139] In still further embodiments, Ra25 is aryl, wherein the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -OH, -0(Ci-C6)alkyl, -SFs, -NHC(0)-(Ci-C6)alkyl, and 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =0. In other embodiments, Ra25 is phenyl, wherein the phenyl is
unsubstituted or substituted with one or more (Ci-Ce)alkyl, wherein each alkyl is
independently unsubstituted or substituted with (Ci-C6)haloalkyl, -OH, -0(Ci-C6)alkyl,
-SFs, -NHC(0)H, -NHC(0)-(Ci-C6)alkyl, =0, -ML·, and -MI(Ci-C6)alkyl.
[0140] In still further embodiments, Ra25 is heteroaryl, wherein the heteroaryl 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
heterocycloalkyl is unsubstituted or substituted with =0.
[0141] In some embodiments, Ra25 is alkynyl. In certain embodiments, Ra25 is (C2- C6)alkynyl.
[0142] In certain embodiments, Ra25 is:
Figure imgf000074_0001
Figure imgf000075_0001
[0143] In certain embodiments, Ra25 is:
Figure imgf000075_0002
[0144] In some embodiments, Ra26 and Ra27 attached to the same carbon form a cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the cycloalkyl is a (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. In certain embodiments, Ra26 and Ra27 attached to the same carbon form an unsubstituted cyclopropyl or cyclobutyl. In some embodiments, Ra26 and Ra27 attached to the same carbon form a cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl are substituted with one or more halo.
[0145] In some embodiments, each Ra26 and Ra27 is hydrogen. In some embodiments, at least one Ra26 or Ra27 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, -ORa32, and -NRa33Ra34. In some embodiments, at least one Ra26 or R327 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, 3- to 6-membered heteroaryl, -OH, -0-(Ci-C6)alkyl, -0-(Ci- C6)haloalkyl, -ML·, -Ml(Ci-C6)alkyl, -N((Ci-C6)alkyl)((Ci-C6)alkyl). In some
embodiments, one Ra26 or one Ra27 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. In certain embodiments, one Ra26 or one Ra27 is (Ci-Ce)alkyl, wherein the alkyl is unsubstituted or substituted with fluoro, chloro, (C3-C6)cycloalkyl, (C3)halocycloalkyl, or -OH. In some embodiments, one Ra26 or one Ra27 is ethyl substituted with difluorocyclopropyl.
[0146] In some embodiments, at least one Ra26 or Ra27 is alkyl substituted with 3- to 10- membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, and =0. In certain embodiments, at least one Ra26 or Ra27 is alkyl substituted with 4- to lO-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and =0. In certain embodiments, the 4- to lO-membered heterocycloalkyl is a polycyclic heterocycloalkyl. In some embodiments, at least one Ra26 or Ra27 is alkyl substituted with 5- to 6-membered heteroaryl.
[0147] In some embodiments, q is 1. In still other embodiments, q is 2. In some embodiments, q is 1, and one of R326 and Ra27 is hydrogen. In other embodiments, q is 2, and one Ra26 and two Ra27 are hydrogen. In other embodiments, q is 2, and two Ra26 and one Ra27 are hydrogen. In some embodiments, q is 2, and two Ra26 and three Ra27 are hydrogen. In some embodiments, q is 2, and three Ra26 and two Ra27 are hydrogen.
[0148] In some embodiments of 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, Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In some embodiments, Ral is hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocydoalkyl. In some embodiments, Ral is hydrogen, (Ci-Ce)alkyl, or (C3-C6)cydoalkyl. In certain embodiments, Ral is hydrogen. In other embodiments, Ral is (Ci-C6)alkyl. For example, in some embodiments, Ral is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, Ral is (C3-C6)cydoalkyl. For example, in some embodiments, Ral is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0149] In some embodiments of 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, Ra2 is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -SCkR310, wherein the alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, each Ra7, Ra8, Ra9, and Ral°, is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
heterocycloalkyl, or haloheterocycloalkyl. In some embodiments, each Ra7, Ra8, Ra9, and Ral°, is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In some embodiments, each Ra7, Ra8, Ra9, and Ral°, 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. In certain embodiments, each Ra7, Ra8, Ra9, and Ral°, is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, or (C3- C6)halocycloalkyl. In some embodiments of 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, Ra2 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. In certain embodiments, Ra2 is hydrogen. In some embodiments, wherein Ra2 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.
[0150] In some embodiments of 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, Ra3 is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein the alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, each Ra7, Ra8, Ra9, and Ral°, is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each Ra7, Ra8, Ra9, and Ral°, is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocydoalkyl. In certain embodiments of 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, Ra3 is hydrogen, fluoro, chloro, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, -NO2, -CN, -SO2NH2, -NH2, -NH(Ci-C6)alkyl, -N((Ci-C6)alkyl)((Ci- Ce)alkyl), -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -SO2H, or -S02-(Ci-C6)alkyl. In certain embodiments, Ra3 is hydrogen. In some embodiments, wherein Ra3 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.
[0151] In some embodiments of 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, each Ra4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo. In some embodiments, each Ra4 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to lO-membered heterocycloalkyl, (C6- Cio)aryl, 5- to lO-membered heteroaryl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, =0, - SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo. In some embodiments, each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl. In certain embodiments, each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3- C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, or 3- to 10- membered haloheterocycloalkyl. In some embodiments, each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocycloalkyl. In some embodiments of 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, each Ra4 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-C6)alkyl), -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -SO2H, =0, and -SO2- (Ci-C6)alkyl. In some embodiments, each Ra4 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. In certain embodiments, at least one Ra4 is fluoro, chloro, bromo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to 6-membered heterocycloalkyl, -NO2, -CN, -SO2NH2, -NH2, -NH(Ci-C6)alkyl, -N((Ci-C6)alkyl)((Ci- C6)alkyl), -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -SO2H, =0, or -S02-(Ci-C6)alkyl.
In some embodiments, at least one Ra4 is fluoro, chloro, bromo, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, or -0-(Ci-C6)haloalkyl. In certain embodiments, at least one Ra4 is fluoro, chloro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2, or -CF3.
[0152] In some embodiments of the compound of Formula (X) or Formula (I), or a pharmaceutically acceptable salt thereof 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.
[0153] In some embodiments of the compound of Formula (X-A), Formula (X-A-i), Formula (X-B), Formula (X-C), Formula (X-C-i), Formula (I-A), Formula (I-A-i), Formula (I-B), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, 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.
[0154] In some embodiments, Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo. In certain embodiments, Ra2 and Ra3 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-C6)alkyl, -0(Ci-C6)alkyl, and -OH. In some embodiments, Ra2 and Ra3 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and -OH. In some embodiments, Ra2 and Ra3 are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, and -OH. In certain embodiments, Ra2 and Ra3 are independently hydrogen, methyl, or ethyl. In some embodiments, Ra2 and Ra3 are both hydrogen. In certain embodiments, one of R32 and Ra3 is (Ci-C6)alkyl.
[0155] In some embodiments of 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), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, Ral and Ra2, together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, Ral and Ra2, 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.
[0156] In some embodiments of the 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, two to four Ra4, 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. In some embodiments, two to four Ra4, together with the atoms to which they are attached, form a (C6-Cio)aryl, 3- to 6-membered heteroaryl, (C3-C6)cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is fused with ring A. In other embodiments, the cycloalkyl or heterocycloalkyl forms a spirocyclic system with ring A. In some embodiments, wherein two to four Ra4, 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 Ra4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN,
-SO2NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo.
[0157] In some embodiments of 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), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, Ra2 and one Ra4, 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. In some embodiments, Ra2 and one Ra4, 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, Ra2 and one Ra4, 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, Ra2 and one Ra4, 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 R32 and Ra4 may be fused to ring A. For example, in some embodiments,
Figure imgf000081_0001
some embodiments, R3 is hydrogen.
[0158] In some embodiments of 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), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, Ra3 and one Ra4, 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. In some embodiments, Ra3 and one Ra4, 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, Ra3 and one Ra4, 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, Ra3 and one Ra4, together with the atoms to which they are attached, form a C3-cycloalkyl. The cycloalkyl or
heterocycloalkyl formed by Ra3 and Ra4 may be fused to ring A. For example, in some embodiments,
Figure imgf000082_0001
some embodiments, Ra2 is hydrogen.
[0159] In some embodiments of 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), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, when X is -S(O)-, -S(0)2-, -S(0)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl. For example, in certain embodiments, Ral and one Ra4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl. For example, in some embodiments,
Figure imgf000082_0002
[0160] In some embodiments, Ra2 or Ra3 is hydrogen. In other embodiments, both of Ra2 and Ra3 are hydrogen. In some embodiments, m is 0. Thus, in some embodiments,
Figure imgf000083_0001
[0161] In some embodiments, when X is -C(O)-, Ral and one Ra4, together with the atoms to which they are attached, form a spirocycle with ring A. In certain embodiments, the spirocycle is unsubstituted. In some embodiments, the spirocycle is substituted with one or more halo.
[0162] It should be understood that in some embodiments, wherein Ra2 and one Ra4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein Ra3 and one Ra4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl; or wherein two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; there may exist one or more other Ra4 independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCte, -CN, -SO2NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently unsubstituted or substituted with one or more halo. For example, in some embodiments of Formula (I), m is 3; Ra2 and one Ra4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining two Ra4 are independently halo or alkyl. In some embodiments of Formula (I- A), Formula (I- A-i), Formula (I-B), or Formula (I-B-i), p is 4; Ra3 and one Ra4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining three Ra4 are independently -OH, halo, alkyl, or haloalkyl.
[0163] In some embodiments of 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), or Formula (I-B-i), or a pharmaceutically acceptable salt thereof, Ra2 and Ra3, 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. For example, in some embodiments, Ra2 and Ra3, 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, Ra2 and Ra3, 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.
[0164] In some embodiments of 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, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-. In some embodiments, X is -S(0)2-, -C(O)-, or -C(Ra6)2-. In certain embodiments, X is -S(O)-, -S(0)2-, or -S(0)NRa46-. In other embodiments, X is -C(S)-, -C(O)-, or -C(Ra6)2-
[0165] In some embodiments of 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, X is -S(O)-.
[0166] In some embodiments of 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, X is -S(0)2-
[0167] In some embodiments of 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, X is -S(0)NRa46-, wherein Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0. In some embodiments, Ra46 is hydrogen or (Ci- C6)alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0. In certain embodiments, Ra46 is hydrogen. In other embodiments, Ra46 is unsubstituted (Ci-Ce)alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In still other embodiments, Ra46 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, (C6-Cio)aryl, 5- to 7-membered heteroaryl, and =0. In still further embodiments, Ra46 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C3-C6)cycloalkyl, and =0.
[0168] In some embodiments of 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, X is -C(S)-.
[0169] In some embodiments of 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, X is -C(O)-.
[0170] In some embodiments, of 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, X is -C(Ra6)2-, wherein each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl. In certain embodiments, each Ra6 is independently hydrogen, halo, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl. In some embodiments, each Ra6 is independently hydrogen, chloro, fluoro, methyl, ethyl, propyl, -CFhF, -CHF2, or -CF3. In some embodiments, each Ra6 is H, and X is -CH2-.
[0171] In some embodiments of 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, X is -S(0)2-, -C(O)-, or -CH2-. [0172] In some embodiments, the compound of Formula (I), Formula (I-A), Formula (I-A- i), Formula (I-B), or Formula (I-B-i), is:
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
, p y acceptable salt of any of these.
[0173] 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) is:
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000112_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
, or a pharmaceutically acceptable salt of any of these.
[0174] In some embodiments, the compound of Formula (I), Formula (I-A), Formula (I-A- i), Formula (I-B), or Formula (I-B-i), is:
Figure imgf000121_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
a pharmaceutically acceptable salt of any of these.
[0175] 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) is:
Figure imgf000135_0002
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000155_0002
Figure imgf000155_0003
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000157_0002
pharmaceutically acceptable salt of any of the foregoing
[0176] 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 Formula (I-C-i), 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)- . The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), or ( R )- and 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). When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. [0177] “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 acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo- glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4- aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p- toluenesulfonic acid, trifluoroacetic acid, or undecylenic acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine,
diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, or N- ethylpiperidine. In some embodiments, 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. [0178] Unless otherwise stated, 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 Formula (I-C-i), or their pharmaceutically acceptable salts, also include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds may have the present structures except for the replacement of a hydrogen by a deuterium (D or 2H) or tritium (¾), or the replacement of a carbon- 12 by a carbon-l3 (13C) or carbon-l4 (14C).
[0179] 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:
Figure imgf000159_0001
[0180] 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. In this scheme, compound I- 102 is combined with 2-chloroethanesulfony chloride, triethylamine (Et3N), 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. This compound can be combined with triethylamine, solvent (such as DCM), and an RB-carbonyl chloride reactant, wherein the RB 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)-. Alternatively, 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
hexafluorophosphate (FtATU), and an RB-COOH reactant, and 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)-. In still another route, compound 1-106 is combined with triethylamine, a solvent (such as DCM), and an RB-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- In some embodiments of any of the these routes, a different solvent is used in one or more steps, such acetonitrile. In some embodiments, a different amine is used. In certain embodiments, the temperature may be adjusted.
[0181] While General Scheme 1-1 depicts the preparation 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, with certain substituents or moieties, other compounds according to the Formulae may also in some embodiments be prepared following analogous reaction schemes. For example, compounds with a 4-, 7- or 8-membered heterocycloalkyl ring A, or compounds with Ra2 or Ra3 other than hydrogen, or other compounds disclosed herein may, in some embodiments, be prepared following analogous reaction schemes. The reactants, solvents, and other compounds used to prepare 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, by following General Reaction Scheme 1-1, or by another route, may be
commercially available or may be prepared following organic chemical techniques.
[0182] Further provided herein is 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.
II. Methods of Treatment
[0183] Provided herein are methods of treating a disorder 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. Also provided are methods of treating a disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 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. In some embodiments, 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.
[0184] 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. [0185] Further provided herein is 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, for use in a method of treating a disorder in a subject in need thereof.
[0186] In some embodiments of the methods and uses provided herein, the disorder is related to K-Ras, for example a disorder associated with a mutation of K-Ras or
dysregulation of K-Ras. In some embodiments of the methods and uses provided herein, the disorder is related to the KRAS gene, for example a disorder associated with a mutation of the KRAS gene or dysregulation of the KRAS gene. Mutation or dysregulation of K-Ras or KRAS may include mutation or dysregulation of human K-Ras4a and/or human K-Ras4b. In some embodiments, the disorder is related to the K-Ras (for example, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, for example a disorder related to aberrant K-Ras signaling pathway activity. In some embodiments, the disorder is related mutation or dysregulation of human K-Ras4b. In certain embodiments, 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.
[0187] In some embodiments, the disorder is neurofibromatosis type 1 (NF1), Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome. In some embodiments, 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,
pheochromocytomas, and breast cancer.
[0188] In some embodiments of the methods and uses provided herein, the disorder is cancer. In some embodiments, the cancer is related to K-Ras, for example a cancer associated with a mutation of K-Ras or dysregulation of K-Ras. In some embodiments of the methods and uses provided herein, 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. In some embodiments, 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. In some embodiments, the cancer is related mutation or dysregulation of human K-Ras4b. In certain embodiments, the cancer is related to aberrant K-Ras4b signaling pathway activity. In some embodiments, the cancer is related mutation or dysregulation of human K-Ras4a. In certain embodiments, the cancer is related to aberrant K-Ras4a signaling pathway activity.
[0189] In some embodiments, 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. Thus, in one aspect, provided herein is 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. In some embodiments, 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.
[0190] In another aspect, provided herein is 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. In still another aspect, provided herein is 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, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof. In a further aspect, 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 reducing the level of a K-Ras protein in a subject in need thereof. In some embodiments of these aspects, 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. 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.
[0191] In some embodiments, 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. 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, 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. In certain embodiments, the post-translational modification that is blocked is farnesylation.
[0192] In another aspect, provided herein is 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. In still another aspect, provided herein is 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, for use in a method of reducing the activity of a K-Ras protein in a subject in need thereof. In a further aspect, 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 reducing the activity of a K-Ras protein in a subject in need thereof. In some embodiments of these aspects, 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.
[0193] In some embodiments, both the activity of K-Ras and the level of K-Ras are reduced in a subject in need thereof. In certain embodiments, the K-Ras is human K-Ras4b. In certain embodiments, the K-Ras is human K-Ras4a.
[0194] “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.
[0195] 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, including the amelioration 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.
[0196] “ 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. 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.
ENUMERATED EMBODIMENTS
[0197] Embodiment 1-1. A compound of Formula (I):
Figure imgf000166_0001
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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0; Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2,
-NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15,
wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo,
-ORa16, =0, -NRal7Ra18,
-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each
Figure imgf000168_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra23, -ORa24, and
-SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NH2, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13; and
n is an integer from 0 to 11.
[0198] 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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, or cycloalkyl, wherein when Ral is alkyl, X is -S(O)-, -S(0)2- , -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N02, -CN, -SOzNTL·, -NRa7Ra8, -ORa9, and -S02Ral°, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N02, -CN, -S02NH2,
-NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, or halocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or Ra2 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ra3 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each aryl, heteroaryl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -SFs, and Ra35, wherein Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-SOzRa57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each
Figure imgf000171_0001
Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each Ral1, Ral2, Ral9, Ra20, and Ra21 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; each Ral3 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral9, Ra20, Ra21, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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,
-NRa22Ra2\ -ORa24, and -SFs; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; and n is an integer from 0 to 11.
[0199] Embodiment 1-3. The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (I- A):
Figure imgf000172_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (I).
[0200] Embodiment 1-4. The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (I-B):
Figure imgf000172_0002
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-,— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
r is 0, 1, or 2;
p is an integer from 0 to 7;
and B, Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (I). [0201] Embodiment 1-5. The compound of Embodiment 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is -CEh-
[0202] 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.
[0203] 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
heterocycloalkyl.
[0204] 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.
[0205] 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.
[0206] 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.
[0207] 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.
[0208] 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 Ra5 are independently selected from the group consisting of halo; -0-(Ci-C4)alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3- C6)cycloalkyl unsubstituted or substituted with one or more fluoro or chloro; and (Ci- C6)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, aryl, heteroaryl, halo, -OH, -0-(Ci-C4)alkyl, =0, -NRa20Ra21, and -CN. [0209] Embodiment 1-13. The compound of any one of Embodiments 1-1 to 1-3, or 1-6 to I- 12, wherein the compound is of Formula (I-A-i):
Figure imgf000174_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7.
[0210] 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 Ra5 is:
Figure imgf000174_0002
wherein:
Ra25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORa28, -SFs, and
-NRa29Ra30;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -SFs, =0, -ORa31,
-NRa41Ra42, -NRa43C(0)Ra44, cycloalkyl, and heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, halo, -OH, and -SFs; each Ra26 and Ra27 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, -ORa32, and
-NRa33Ra34; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =0, and -SFs; or one Ra26 and one R327 attached to the same atom, 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 Ra2X, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra41, Ra42, Ra43, and Ra44 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
[0211] Embodiment 1-15. The compound of Embodiment 1-14, or a pharmaceutically acceptable salt thereof, wherein q is 1 and Ra26 is hydrogen.
[0212] 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 Ra5 is heteroaryl or
heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -SFs, and Ra35.
[0213] Embodiment 1-17. The compound of Embodiment 1-14, or a pharmaceutically acceptable salt thereof, wherein Ra35 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs. [0214] Embodiment 1-18. The compound of any one of Embodiments 1-1 to 1-17, or a pharmaceutically acceptable salt thereof, wherein Ra2 and Ra3, together with the atom to which they are attached, form a (C3-Cs)cycloalkyl or a 3- to 5-membered heterocycloalkyl.
[0215] 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 Ral and one Ra4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
[0216] Embodiment 1-20. The compound of any one of Embodiments 1-1 to 1-17, or a pharmaceutically acceptable salt thereof, wherein Ra2 and one Ra4, together with the atoms to which they are attached, form a (C3-C6)cycloalkyl or a 3- to 6-membered heterocycloalkyl.
[0217] 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 Ra2 and Ra3 are each hydrogen.
[0218] 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-
[0219] Embodiment 1-23. 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)-.
[0220] Embodiment 1-24. 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 -CEb-
[0221] 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.
[0222] 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.
[0223] 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.
[0224] 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. [0225] 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.
[0226] Embodiment 1-30. A compound of Embodiment 1-1, wherein the compound is:
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000178_0002
pharmaceutically acceptable salt of any of the foregoing. [0227] Embodiment 1-31. 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.
[0228] 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.
[0229] Embodiment 1-33. The method of Embodiment 1-32, wherein the K-Ras protein is human K-Ras4b.
[0230] 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.
[0231] Embodiment 1-35. The method of Embodiment 1-34, wherein the disorder is cancer.
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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. [0236] Embodiment 1-40. The use of Embodiment 1-39, wherein the K-Ras protein is human K-Ras4b.
[0237] Embodiment 1-41. 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.
[0238] Embodiment 1-42. The use of Embodiment 1-41, wherein the disorder is cancer.
[0239] 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.
[0240] 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.
[0241] 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.
[0242] 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.
[0243] Embodiment 1-47. The compound for use of Embodiment 1-46, wherein the K-Ras protein is human K-Ras4b.
[0244] 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.
[0245] Embodiment 1-49. The compound for use in Embodiment 1-48, wherein the disorder is cancer.
[0246] 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.
[0247] 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.
[0248] 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.
[0249] Embodiment II-1. A compound of Formula (X):
Figure imgf000181_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rxl, Rx2, and Rx3 are independently hydrogen, -CN, or alkyl; or Rx2 and Rx3 together form alkenyl; or Rxl and Rx2 together with the carbon atoms to which they are attached form heteroaryl, heterocycloalkenyl, or cycloalkenyl; or Ral and Rx2 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 -ORx4, wherein each Rx4 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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2- wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein when A is phenyl, Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, cycloalkyl,
heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently
unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, 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)-, Ral and one Ra4, together with the atoms to which they are attached, form a spirocycle with ring A, wherein the spirocycle is
unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -N02, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein 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, -ORa16, =0, -NRal7Ral8,-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each
Figure imgf000183_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, Ra35, Ra54, and Ra55, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra2\ -ORa24, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, and Ra39 is independently hydrogen, alkyl, or haloalkyl;
wherein each alkyl or haloalkyl or Ra22 and Ra23 is independently
unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which 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 Ra40 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. [0250] Embodiment II-2. The compound of Embodiment II- 1, wherein the compound is of Formula (X-I):
Figure imgf000185_0001
or a pharmaceutically acceptable salt thereof, wherein A is 4- to lO-membered heterocycloalkyl, and B, X, Rxl, Rx2, Rx3, Ral, R32, Ra3, Ra4, Ra5, m, and n are as defined for Formula (X).
[0251] Embodiment II-3. The compound of Embodiment II- 1 or II-2, wherein the compound is of Formula (X-A):
Figure imgf000185_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, R5 2, Rx3, Ral, R32, Ra3, Ra4, Ra5, and n are as defined for Formula (X). [0252] Embodiment II-4. The compound of Embodiment II-1 or II-2, wherein the compound is of Formula (X-C):
Figure imgf000186_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, R52, Rx3, Ral, R32, Ra3, Ra4, Ra5, and n are as defined for Formula (X).
[0253] Embodiment II-5. The compound of Embodiment II- 1 or II-2, wherein the compound is of Formula (X-B):
Figure imgf000186_0002
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-,— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6 ‘)2— , wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
r is 0, 1, or 2; p is an integer from 0 to 7;
Figure imgf000186_0003
are as defined for Formula
(X). [0254] Embodiment II-6. The compound of Embodiment II- 1, wherein the compound is of Formula (I):
Figure imgf000187_0001
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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N02, -CN, -SOzNEb, -NRa7Ra8, -ORa9, and -S02Ral°, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N02, -CN, -SOzNEb, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo,
-ORa16, =0, -NRal7Ra18,
-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-SOzRa57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each
Figure imgf000189_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra23,
-ORa24, and -SFs; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NH2, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; and n is an integer from 0 to 11. [0255] Embodiment II-7. The compound of Embodiment II-6, 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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, or cycloalkyl, wherein when Ral is alkyl, X is -S(O)-, -S(0)2- , -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N02, -CN, -SOzNEb, -NRa7Ra8, -ORa9, and -S02Ral°, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N02, -CN, -SOzNEb, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, or halocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or Ra2 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ra3 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each aryl, heteroaryl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -SFs, and Ra35, wherein Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Ral4 Ral5 Ral6 Ral7 Ral8 Ra48 J^a49 p^aSO p^aS I p^a52 p^aSS p^a54 p^aSS
Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each Ral1, Ral2, Ral9, Ra20, and Ra21 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; each Ral3 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral 1, Ral2, Ral3, Ral9, Ra20, Ra21, and Ra35, and each cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl of Ra58 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,
-NRa22Ra23, -ORa24, and -SFs; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NH2, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; and n is an integer from 0 to 1 1.
[0256] Embodiment II-8. The compound of Embodiment II-6 or II-7, wherein the compound is of Formula (I- A):
Figure imgf000192_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Ral, R32, Ra3, Ra4, Ra5, and n are as defined for Formula (I).
[0257] Embodiment II-9. The compound of Embodiment II-6 or II-7, wherein the compound is of Formula (I-B):
Figure imgf000193_0001
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-,— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; r is 0, 1, or 2; p is an integer from 0 to 7; and B, Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (I).
[0258] Embodiment II- 10. The compound of Embodiment II-5 or II-9, or a
pharmaceutically acceptable salt thereof, wherein Y is -CEh-
[0259] 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.
[0260] Embodiment 11-12. The compound of Embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heteroaryl.
[0261] 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
heterocycloalkyl. [0262] 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.
[0263] 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.
[0264] 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.
[0265] 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.
[0266] 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.
[0267] 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 Ra5 is:
unsubstituted or substituted alkyl, wherein the alkyl is branched;
-NRallRa12, wherein at least one of Ral1 and Ral2 is not hydrogen; or
(Ci-C2)alkyl substituted with one or more substituents independently selected from the group consisting of =0, -NRa20Ra21, and Ra58, wherein Ra58 is heterocycloalkyl and at least one of Ra20 and Ra21 is not hydrogen.
[0268] Embodiment 11-20. The compound of Embodiment 11-19, or a pharmaceutically acceptable salt thereof, wherein both Ral1 and Ral2 are not hydrogen.
[0269] Embodiment 11-21. The compound of Embodiment 11-19 or 11-20, or a
pharmaceutically acceptable salt thereof, wherein at least one of Ral1 and Ral2 is substituted alkyl. [0270] Embodiment 11-22. The compound of any one of Embodiments 11-19 to 11-21, or a pharmaceutically acceptable salt thereof, wherein Ral1 is alkyl substituted with aryl, wherein the aryl is unsubstituted or substituted.
[0271] Embodiment 11-23. The compound of any one of Embodiments 11-19 to 11-22, or a pharmaceutically acceptable salt thereof, wherein Ral2 is alkyl substituted with one or more substituents independently selected from the group consisting of =0, -NRa22Ra2\ -ORa24, and heterocycloalkyl, wherein the heterocycloalkyl is independently unsubstituted or substituted.
[0272] Embodiment 11-24. The compound of Embodiment 11-19, or a pharmaceutically acceptable salt thereof, wherein at least one Ra5 is Ci-alkyl substituted with -NRa20Ra2 1, wherein at least one of Ra20 and Ra21 is not hydrogen.
[0273] Embodiment 11-25. The compound of Embodiment 11-19, or a pharmaceutically acceptable salt thereof, wherein at least one Ra5 is C2-alkyl substituted with =0 and - NRa20Ra21, wherejn a\ least one of Ra20 and Ra21 is not hydrogen.
[0274] Embodiment 11-26. The compound of Embodiment 11-19, or a pharmaceutically acceptable salt thereof, wherein at least one Ra5 is substituted alkyl, wherein the alkyl is isopropyl, wherein the isopropyl is substituted with two or more substituents independently selected from the group consisting of =0, -NRa20Ra21, -ORa19, and Ra58; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkynyl, -CN, and =0, and wherein each alkyl is independently unsubstituted or substituted with one or more halo.
[0275] Embodiment 11-27. The compound of any one of Embodiments 11-19 or 11-24 to II- 26, or a pharmaceutically acceptable salt thereof, wherein Ra20 and Ra21 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 with one or more substituents independently selected from the group consisting of halo, =0, -NRa22Ra2\ — ORa24, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; wherein 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, haloalkyl, and -NRa36Ra37; and wherein at least one of Ra20 and Ra21 is not hydrogen.
[0276] Embodiment 11-28. The compound of Embodiment 11-27, or a pharmaceutically acceptable salt thereof, wherein both Ra20 and Ra21 are not hydrogen.
[0277] 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 Ra5 is -NRallRa12, wherein:
Ral1 is Ci-alkyl substituted with aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and
Ral2 is hydrogen or alkyl, wherein the alkyl is substituted with one or more substituents independently selected from the group consisting of =0, aryl, heteroaryl, -
NRa22Ra23, and
-ORa24;
wherein 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.
[0278] 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 Ra5 is a substituted alkyl of formula (a):
Figure imgf000196_0001
wherein:
w is 0 or 1;
Ra20 and Ra21 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 independently selected from the group consisting of halo, =0, -NRa22Ra2\ -ORa24, 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.
[0279] Embodiment 11-31. The compound of any one of Embodiments II- 1 to 11-18, or a pharmaceutically acceptable salt thereof, wherein one or more Ra5 is alkyl, wherein the alkyl is isopropyl, wherein each terminal methyl of the isopropyl is independently substituted with one or more substituents independently selected from the group consisting of =0, -NRa20Ra2 1,
-ORa19, and Ra58; wherein each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of Ra58 is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -CN, alkynyl, halo, and alkyl, and wherein each alkyl is independently unsubstituted or substituted with one or more halo.
[0280] 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.
[0281] Embodiment 11-33. The compound of Embodiment II-31 or 11-32, or a
pharmaceutically acceptable salt thereof, wherein one terminal methyl of the isopropyl is substituted with =0 and -NRa20Ra21 or =0 and Ra58, wherein Ra58 is heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted.
[0282] Embodiment 11-34. The compound of any one of Embodiments II- 1 to 11-18, or a pharmaceutically acceptable salt thereof, wherein one or more Ra5 are independently selected from the group consisting of halo; -0-(Ci-C4)alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3- C6)cycloalkyl unsubstituted or substituted with one or more fluoro or chloro; and (Ci- C6)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, aryl, heteroaryl, halo, -OH, -0-(Ci-C4)alkyl, =0,
— NRa20Ra21 , and -CN.
[0283] 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):
Figure imgf000198_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X).
[0284] 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):
Figure imgf000198_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7.
[0285] 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):
Figure imgf000199_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X).
[0286] 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 Ra5 is:
Figure imgf000199_0002
wherein:
Ra25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORa28, -SFs, and
-NRa29Ra30;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -SFs, =0, -ORa31,
-NRa41Ra42, -NRa43C(0)Ra44, cycloalkyl, and heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, halo,
-OH, and -SFs; each Ra26 and Ra27 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, -ORa32, and
-NRa33Ra34; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =0, and -SFs; or one Ra26 and one R327 attached to the same atom, 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 Ra2X, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra41, Ra42, Ra43, and Ra44 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
[0287] Embodiment 11-39. The compound of Embodiment 11-38, or a pharmaceutically acceptable salt thereof, wherein q is 1 and Ra26 is hydrogen.
[0288] Embodiment 11-40. The compound of any one of Embodiments II- 1 to 11-18 or II- 34 to 11-39, or a pharmaceutically acceptable salt thereof, wherein at least one Ra5 is heteroaryl or heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -SFs, and Ra35.
[0289] Embodiment 11-41. The compound of Embodiment 11-40, or a pharmaceutically acceptable salt thereof, wherein Ra35 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs. [0290] Embodiment 11-42. The compound of any one of Embodiments II- 1 to 11-41, or a pharmaceutically acceptable salt thereof, wherein Ra2 and Ra3, together with the atom to which they are attached, form a (C3-Cs)cycloalkyl or a 3- to 5-membered heterocycloalkyl.
[0291] 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 Ral and one Ra4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
[0292] Embodiment 11-44. The compound of any one of Embodiments II- 1 to 11-41, or a pharmaceutically acceptable salt thereof, wherein Ra2 and one Ra4, together with the atoms to which they are attached, form a (C3-C6)cycloalkyl or a 3- to 6-membered heterocycloalkyl.
[0293] 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 Ra2 and Ra3 are each hydrogen.
[0294] 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-
[0295] 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)-.
[0296] 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-
[0297] 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.
[0298] 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.
[0299] 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.
[0300] 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. [0301] 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.
[0302] 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 Rxl is hydrogen.
[0303] 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 Rx2 and Rx3 are hydrogen.
[0304] 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 Rxl, Rx2, and Rx3 is unsubstituted or substituted alkyl.
[0305] Embodiment 11-57. The compound of Embodiment II- 1, wherein the compound is:
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
pharmaceutically acceptable salt of any of the foregoing.
[0306] Embodiment 11-58. The compound of Embodiment II- 1 or II-6, wherein the compound is:
Figure imgf000204_0002
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000206_0002
pharmaceutically acceptable salt of any of the foregoing.
[0307] Embodiment 11-59. The compound of Embodiment II- 1 or II-6, wherein the compound is:
Figure imgf000206_0003
Figure imgf000207_0001
Figure imgf000207_0002
pharmaceutically acceptable salt of any of the foregoing.
[0308] Embodiment 11-60. The compound of Embodiment II- 1, wherein the compound is:
Figure imgf000207_0003
Figure imgf000208_0001
Figure imgf000208_0002
pharmaceutically acceptable salt of any of the foregoing.
[0309] 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. [0310] 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.
[0311] Embodiment 11-63. The method of Embodiment 11-62, wherein the K-Ras protein is human K-Ras4b.
[0312] Embodiment II-63-ii. The use of Embodiment 11-62, wherein the K-Ras protein is human K-Ras4a.
[0313] 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.
[0314] Embodiment 11-65. The method of Embodiment 11-64, wherein the disorder is cancer.
[0315] 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.
[0316] 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.
[0317] 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.
[0318] 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. [0319] Embodiment 11-70. The use of Embodiment 11-69, wherein the K-Ras protein is human K-Ras4b.
[0320] Embodiment II-70-ii. The use of Embodiment 11-69, wherein the K-Ras protein is human K-Ras4a.
[0321] 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.
[0322] Embodiment 11-72. The use of Embodiment 11-71, wherein the disorder is cancer.
[0323] 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.
[0324] 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.
[0325] 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.
[0326] 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.
[0327] Embodiment 11-77. The compound for use of Embodiment 11-76, wherein the K- Ras protein is human K-Ras4b.
[0328] Embodiment II-77-ii. The use of Embodiment 11-76, wherein the K-Ras protein is human K-Ras4a.
[0329] 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. [0330] Embodiment 11-79. The compound for use in Embodiment 11-78, wherein the disorder is cancer.
[0331] 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.
[0332] 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.
[0333] 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.
EXAMPLES
[0334] The following Examples are merely illustrative and are not meant to limit any aspects of the present disclosure in any way.
Example 1-1: Synthesis of (X)-terf-butyl 3-(vinylsulfonamidomethyl)pyrrolidine-l- carboxylate
Figure imgf000211_0001
Boc Boc
[0335] A mixture of (R)-tert- butyl 3-(aminomethyl)pyrrolidine-l-carboxylate (10.0 g, 49.9 mmol) in anhydrous dichloromethane (180 mL) was cooled to 0 °C under an inert atmosphere. 2-chloroethanesulfonyl chloride (4.8 mL, 46.2 mmol) was added with stirring followed by gradual addition of Et3N (13.9 mL, 99.9 mmol) maintaining a temperature below 5 °C to give a thick white suspension. The reaction mixture was stirred at 0 °C for 1 h, then additional Et3N (13.9 mL, 99.9 mmol) was added. The resulting orange suspension was warmed to room temperature and stirred overnight. The mixture was transferred to a separating funnel, and washed with 1 N HC1 (2 x 100 mL) and water (100 mL), then dried (Na2S04), filtered, and the solvent removed under vacuum. The residue was adsorbed onto silica gel (21 g) and purified though silica gel (2 x l20g cartridge) using EtO Ac/hexanes (1 :9 to 7:3) as eluent to give the product (7.71 g) as an oil. Rf (product) = 0.57 (3:2
EtO Ac/hexanes, using KMn04 stain)
Example 1-2: Synthesis of (A)-/V-(pyrrolidin-3-ylmethyl)ethenesulfonamide
trifluoroacetic acid salt
Figure imgf000212_0001
Boc
[0336] A solution of (S)-tert- butyl 3-(vinylsulfonamidomethyl)pyrrolidine-l-carboxylate (1.0 g, 3.4 mmol) in anhydrous dichloromethane (40 mL) was cooled to 0 °C. Trifluoroacetic acid (7.4 mL, 68.9 mmol) was added, and the mixture stirred at room temperature for 2h. The mixture was concentrated to dryness to give a light yellow oil, which was used without further purification. KMn04 stain was used for visualization.
Example 1-3: Synthesis of Formula (I) compounds comprising a pyrrolidinyl, heteroaryl, and carbonyl linker
Figure imgf000212_0002
[0337] To a stirred solution of C.V)-/V-(pyrrolidin-3-ylmethyl)ethenesulfonamide
trifluoroacetic acid salt (80 mg, 0.30 mmol) in MeCN (1.0 mL) was added a solution of the desired heteroaryl acid chloride (0.26 mmol) in MeCN (0.5 mL) followed by Et3N (0.15 mL,
1.1 mmol). The reaction mixture was stirred at room temperature for 3h, resulting in consumption of the starting material (confirmed by TLC). The crude reaction mixture was purified by Medium Pressure Liquid Chromatography on reverse-phase using 20-90 % MeCN/EhO (FLO mobile-phase contained 0.1% TFA) as eluent to give the product. Example 1-4: Synthesis of Formula (I) compounds comprising a pyrrolidinyl, heteroaryl, and SO2 linker
Figure imgf000213_0001
[0338] To a stirred solution of fV)-A-(pyrrolidin-3-yl ethyl)ethenesulfonamide
trifluoroacetic acid salt (80 mg, 0.30 mmol) in MeCN (1.0 mL) was added a solution of the desired sulfonyl chloride (0.26 mmol) in MeCN (0.5 mL) followed by Et3N (0.15 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 3h, resulting in
consumption of the starting material (confirmed by TLC). The crude reaction mixture was purified by Medium Pressure Liquid Chromatography on reverse-phase using 20-90 % MeCN/ELO (H2O mobile-phase contained 0.1% TFA) as eluent to give the product.
Example 1-5: Synthesis of (A)-terf-butyl 3-(vinylsulfonamidomethyl)piperidine-l- carboxylate
Figure imgf000213_0002
Boc Boc
[0339] A solution of (R)-tert- butyl 3-(aminomethyl)piperidine-l-carboxylate (25.0 g, 116.7 mmol) in anhydrous dichloromethane (180 mL) was cooled to 0 °C under an inert atmosphere. 2-chloroethanesulfonyl chloride (12.1 mL, 115.5 mmol) was added with stirring followed by gradual addition of Et3N (34.8 mL, 249.6 mmol) maintaining a temperature below 5 °C to give a thick white suspension. The reaction mixture was stirred at 0 °C for lh, then additional Et3N (34.8 mL, 249.6 mmol) was added. The resulting orange suspension was warmed to room temperature and stirred overnight. The mixture was transferred to a separating funnel, and washed with 1N HC1 (2 x 100 mL) and water (100 mL), then dried (Na2S04), filtered and the solvent removed under vacuum. The residue was adsorbed onto silica gel (21 g) and purified though silica gel (2 x l20g cartridge) using EtO Ac/hexanes (1 :9 to 7:3) as eluent to give the product as an oil. Rf (product) = 0.57 (3:2 EtO Ac/hexanes; using KMn04 for visualization) Example 1-6: Synthesis of (A)-/V-(piperidin-3-ylmethyl)ethenesulfonamide trifluoroacetic acid salt
Figure imgf000214_0001
Boc
[0340] A solution of (S)-tert- butyl 3-(vinylsulfonamidomethyl)piperidine-l-carboxylate (2.0 g, 6.6 mmol) in anhydrous dichloromethane (80 mL) was cooled to 0 °C. Trifluoroacetic acid (14.2 mL, 131.4 mmol) was added, and the mixture stirred at room temperature for 3h. The mixture was concentrated to dryness to give a light yellow oil, which was used without further purification.
Example 1-7: Synthesis of Formula (I) compounds with piperidinyl, heteroaryl, and carbonyl linker
Figure imgf000214_0002
[0341] To a solution of (ri)-/V-(piperidin-3-ylmethyl)ethenesulfonamide trifluoroacetic acid salt (84 mg, 0.30 mmol) in MeCN (1.0 mL) was added a solution of the desired heteroaryl acid chloride (0.26 mmol) in MeCN (0.5 mL) followed by Et3N (0.15 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 3h, resulting in consumption of the starting material (confirmed by TLC). The crude reaction mixture was purified by Medium Pressure Liquid Chromatography on reverse-phase using 20-90 % MeCN/FFO (LLO mobile- phase contained 0.1% TFA) as eluent to give the desired product.
Example 1-8: Synthesis of Formula (I) compounds with piperidinyl, heteroaryl, and SO2 linker
Figure imgf000214_0003
[0342] To a stirred solution of (ri)-/V-(piperi din-3 -ylmethyl)ethenesulfonamide
trifluoroacetic acid salt (84 mg, 0.30 mmol) in MeCN (1.0 mL) was added a solution of the desired aryl sulfonyl chloride (0.26 mmol) in MeCN (0.5 mL) followed by Et3N (0.15 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 3h, resulting in consumption of the starting material (confirmed by TLC). The crude reaction mixture was purified by Medium Pressure Liquid Chromatography on reverse-phase using 20-90 % MeCN/EhO (EhO mobile-phase contained 0.1% TFA) as eluent to give the desired product.
[0343] Compounds synthesized using methods similar to those described in the above Examples are provided in Table 1-1 and Table 1-2 below.
Table 1-1. Synthesized Compounds
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Table 1-2. Synthesized Compounds
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000235_0001
Table 1-3. Characterization of synthesized compounds
Figure imgf000235_0002
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0002
Example 1-9: Covalent modification analysis using Matrix Assisted Laser
Desorption/Ionization - Time of Flight Mass Spectrometry (MALDI-TOF MS)
[0344] Compounds of the synthesized library were evaluated for covalent modification of K-Ras4b 1-188 protein using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), which confirmed covalent labeling at Cl 85 by many of the synthesized compounds.
[0345] Reaction: 20 mM of K-Ras4b (1-188) protein (Protein Expression Laboratory, FNLCR/Leidos Biomed.) in 20 mM HEPES buffer containing 150 mM NaCl, 1 mM AlgCb, pH 7.3 was prepared freshly before assay. 20 mΐ aliquots of protein were dispensed in a 384- well polypropylene plate, then compounds to be tested (0.8 mΐ, 10 mM in DMSO) were added to different wells. For each assay, three blank and three control samples were prepared by mixing 20 mΐ of protein solution with 0.8 mΐ DMSO or 10 mM standard compound (below). The contents of the wells were mixed by aspiration, then the plate was sealed by adhesive cover, centrifuged at 2000 g for 1 minute, and incubated in the dark at room temperature for 24 h.
Figure imgf000251_0001
Standard Compound
[0346] Target plate pretreatment: Before each assay, the MALDI target plate (Bruker MTP 384 ground steel BC) was pre-treated by pipetting 1 mΐ of saturated sinapinic acid in acetonitrile (ACN) onto each spot. This may improve the uniformity of sample
crystallization across the plate, enhancing sensitivity. [0347] Sample preparation: After the 24 h reaction described above, 2 mΐ of the reaction mixture was pipetted into 20 mΐ of MALDI matrix solution (saturated solution of sinapinic acid in 1 : 1 ACN:water solution containing 0.75% trifluoroacetic acid (TFA)) and deposited on a 384 well polypropylene MALDI plate. The resulting solution was mixed by aspiration, centrifuged at 2000 g for 1 minute, then 2 mΐ aliquots were dispensed onto the pre-treated MALDI target plate described above using a Beckman Coulter Biomek FXP 96/Span-8 Laboratory Automation Workstation. The MALDI target plate was dried under mild vacuum to produce spots with fine crystalline structure.
[0348] Measurements: MALDI-TOF measurements were performed on a Bruker Daltonics ultraflex III TOF-TOF mass spectrometer using linear mode and mass range from 5 to 45 kDa. Detector gain was set to x9 (1734 V), sample rate to 1 GS/s, smart beam parameter set: 3_medium was used, and the laser frequency was 66.7 Hz. Spectra were automatically collected using a custom AutoXecute method. Laser power was auto-adjusted using fuzzy control. The peak selection range was set to be between 20500 and 23000 Da. Peak evaluation used half width parameter set to be smaller than 30 Da. Fuzzy control used Proteins/Oligonucleotides protocol with minimum half width 1/6 times above threshold. Up to 1500 shots were collected in 500 shot steps. Dynamic termination was implemented to finish data collection when peak intensity was reaching value of 1200 [a.u.].
[0349] Spectra processing: Spectra were smoothed by SavitzkyGolay algorithm using 12 m/z width and six cycles. Centroid peak detection algorithm was used with signal to noise threshold set to 11, relative intensity threshold 5%, minimum intensity threshold 50 [a.u.], peak width 20 m/z and TopHat baseline subtraction. Peak intensity and area under the peak were evaluated and recorded for all peaks between 21,460 Da and 23,500 Da.
Table 1-4. Percent modification by compounds after 24 h with K-Ras4b(l-l88) GDP no TCEP, as evaluated with MALDI.
Figure imgf000252_0001
Figure imgf000254_0001
Example 1-10: Cell proliferation assays
[0350] Compounds of the synthesized library were also evaluated using cell-based using a mouse embryonic fibroblast (MEF) cell line panel containing single RAS transgene alleles. These MEFs are endogenous HRAS , NRAS and KRAS null, and their growth is completely dependent on exogenous RAS or activated MAPK pathway genes. By adding back specific isoforms of RAS genes or other pathway activators, cell lines were developed which are completely dependent on these genes, but maintain a similar isogenic background. The MEF panel used included all of the major oncogenic mutants of K-Ras4b as well as wild type alleles of the other Ras isoforms (e.g. K-Ras4b G12D, K-Ras4b G12V, K-Ras4b Q61R, H- Ras WT). The control cell line was KRAS G12D MEF that carries C185S mutation
(preventing post translational modification by farnesyl), and membrane attachment necessary for K-Ras signaling is enabled through N-terminal myristoyl moiety (Myr-K-Ras
G12D/C185S). Cell viability in the presence of synthesized compounds was measured using CellTiter-Glo® (Promega). [0351] Cells were plated in black-walled 384-well plates (Greiner, 781091) at densities in accordance with their doubling time (for MEFs typically 1,000 cells/well in 20 mΐ), using the Multidrop Combi Reagent Dispenser (Thermo). They were then incubated overnight at 37°C in a humidified atmosphere of 5% CO2 prior to drug addition. Compound and DMSO addition to microplates was performed using the Access™ Laboratory Workstation
(Labcyte®) and Echo 555 (Labcyte®) liquid handler. Source plates with compounds and DMSO were prepared, and the Echo 555 was used to transfer 50 nL of compound, DMSO, or combination to the appropriate wells. Five pL of complete culture medium was added to all wells of the microplate after compound addition. The highest final compound concentration in each assay was 100 mM or 50 pM with between seven to 12 dilutions. The final DMSO concentration in all wells was 0.2%.
[0352] Cells were incubated with compounds for 72h. All conditions were done in triplicate and experiments performed at least thrice. Cellular ATP levels (an indicator of cell count) were determined with the CellTiter-Glo (CTG, Promega G7573) luminescence assay, using an EnVision Plate Reader (PerkinElmer).
[0353] Plates were harvested at two time points. At the time of drug addition, one plate for each cell line with no compounds added received 5 pL of media and were harvested to represent a measurement of the cell population at the time of compound addition (TO). After 72 h incubation, the compound-treated plates were harvested using CTG reagent and the luminescence was read using the EnVision giving control growth (C) and compound treated well (T72) measurements. Growth inhibition was calculated by:
772 - TO
———— x 100
C - TO
[0354] Dose-response curves were generated using Prism 7 software (GraphPad).
[0355] It was observed that compounds with a pyrrolidinyl A ring, SO2 linker X, and benzene B ring with 4-position substitution (pyrrolidine-sulfonamide compounds substituted at the 4-position of the benzene ring) appeared to have desired biological activity, showing some selectivity towards MEF cell lines expressing KRAS4b mutant versus Myr-KRAS4b G12D OY HRAS cells (e.g., compounds 1-0001105, 1-0001114, 1-0001289, and 1-0001543).
[0356] Results from cell proliferation assays with selected compounds is tabulated in FIGS. 5A-5D (MEF cells, 72h incubation , IC50 values (pM)). FIGS. 8A-8C are heat maps comparing IC50 values for selected compounds. In FIG. 8A, 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. In FIG. 8C, bracketed compounds demonstrated higher activity in MEFs expressing KRAS4b G12V , compared to KRAS4a, HRAS , or Myr-KRAS G12D/C185S cells.
Example 1-11: Comparative Cell Proliferation Assays
[0357] Growth rates of KRAS4b G12D MEF line, and the control MEF line Myr-KRAS G12D/C185S cells in presence of selected were compared. The control cells expressed KRAS protein bearing a C185S mutation that prevents post translational modification by farnesyl. Membrane attachment of Myr-K-Ras G12D/C185S is achieved through N-terminal myristoyl moiety. MAPK signaling in these cells does not differ from other MEF lines, including KRAS4b G12D. Since Cl 85 in K-Ras in these cells is not available for covalent modification, any growth arrest after treatment with a compound indicates off target toxicity.
[0358] Cells were treated with an increasing concentration of a compound (1-100 mM) for 72 h, then cell number was assessed using CTG (Promega). IC50 values were calculated using GraphPad Prism software, and IC50 ratios of K-Ras4b G12D to Myr-K-Ras
G12D/C185 were calculated. An IC50 ratio equal to 1 indicates similar responses of both cell lines to the compound. An IC50 ratio lower than 1 suggests selectivity towards K-Ras4b G12D. These values are listed in FIG. 6.
[0359] Levels of covalent modification to Cl 85 (measured by MALDI-TOF MS) were correlated with calculated IC50 ratios. Compounds 1-0001219, 1-0001086, 1-0001114, 1- 0001285, 1-0001277, 1-0001289, 1-0001377, 1-0001247, 1-0001105, 1-0001282, 1-0001381, 1- 0001098, 1-0001107 demonstrated a desirable level of covalent modification to Cl 85, and IC50 ratios 0.6 or below, suggesting on-target activity (FIG. 7, box within the graph). A number of these compounds are 4-substituted analogues.
Example 1-12: Immunoblot analysis
[0360] Certain compounds of the synthesized library were evaluated for effect on localization of K-Ras in cell membranes. [0361] Cells (MEF KRAS Q61R, KRAS G12D, and Myr-KRAS G12D/C185S) were rinsed trice with ice-cold PBS and then were lysed on ice with ice-cold TNE buffer supplemented with Halt protease and phosphatase inhibitors (Thermo Scientific). This was then centrifuged at 15,000 for 15 minutes to collect whole-cell lysates. Protein concentration was measured with the BCA protein assay (Pierce). Thirty micrograms of total protein per sample was loaded into 4%-l2% NuPAGE Bis-Tris gradient gels (Life Technologies) and separated by SDS-PAGE. Proteins were transferred to polyvinylidene difluoride (PVDF) membranes.
The following antibodies were used for immunoblotting: mouse monoclonal anti-K-Ras (Sigma WH0003845M1, clone 3B10-2F2), mouse anti-RAS (Thermo 1862335), rabbit anti- pERKl/2 (T202/Y204; Cell Signaling Technology 4370), mouse anti-ERKl/2 (Cell
Signaling Technlogy 4696), rabbit anti-p-MEKl/2 (S217/221; Cell Signaling Technology 9154), mouse anti-MEKl/2 (Cell Signaling Technology 4694), rabbit anti-p-AKT (S473; Cell Signaling Technology 4060), mouse anti-AKT (Cell Signaling Technology 2920). Vinculin (rabbit anti-vinculin, Cell Signaling Technology 4650) was used as a loading control.
Primary antibodies were detected with fluorescence-conjugated (LI-COR) secondary antibodies. 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 K-Ras Q61R, K-Ras G12D, or Myr-K-Ras G12D/C185S proteins.
[0362] For the cell fractionation experiments, cells (MEF KRAS G12D, KRAS G12V, and KRAS WT) were seeded at 2xl05 onto lO-cm Petri dishes and allowed to grow for 24 h.
Compounds were added to the medium to a final concentration 10 - 30 mM for 72h. Cells were rinsed three times with ice-cold PBS, then digitonin [300 mΐ of 190 mg/ml in lysis buffer (PBS containing 75 mM KC1, 250 mM sucrose and Halt protease and phosphatase inhibitors (Thermo)] was added for 10 min on ice. Cells were then scraped gently and centrifuged 10 min at 12,000 at 4 °C. The supernatant (cytosolic fraction) was removed, and the remaining pellet (membrane fraction) was resuspended in 100 mΐ of TNE lysis buffer (25 mM HEPES buffer containing 150 mM NaCl, 5 mM MgCl2, 1% SDS, 10% glycerol, 2.5 mM EDTA, supplemented with Halt protease and phosphatase inhibitors) and allowed to incubate for 30 min before processing with standard immunoblot protocol. The following antibodies were used: mouse monoclonal anti-KRAS (Sigma WH0003845M1, clone 3B10-2F2), mouse anti- RAS (Thermo 1862335), mouse anti-MEKl/2 (Cell Signaling Technology 4694) as a loading control for cytosolic fraction, and rabbit anti-Na,K-ATPase (Cell Signaling Technology 3010) as a loading control for membrane fraction. 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). “WCL” refers to whole cell lysate.
[0363] Results from the immunoblot (Western blot) analysis in MEF cells for selected compounds are shown in Table 1-5 below.
Table 1-5. Western blot analysis, MEFs, DMSO Ctrl = 100
Figure imgf000258_0001
Figure imgf000259_0001
Example 1-13: Confocal visualization of KRAS localization
[0364] HeLa cells expressing tet-inducible eGFP-KRAS4b G12D in a lentiviral expression vector were used for confocal imaging. The transgene expression was induced with 200 ng/ml doxycycline, followed immediately with addition of the compound directly to the growth medium, at final concentrations depicted on the image (FIG. 3, numbers on image indicate specific concentrations of compound). Cells were treated with compound for 48 hours (re-dosed at 24 hr). Cells were then fixed with 4% paraformaldehyde (Electron
Microscopy Sciences), and counterstained with 1 pg/ml Hoechst (Cell Signaling) and 5 pg/ml of ConcanavainA-Alexa647 (Thermo Fisher Scientific). Images were acquired with a Crestoptics spinning disk confocal on a Nikon Eclipse-TI inverted microscope and a Plan Apo 20x/0.75 N.A. objective. Images were taken after 48h induction of KRAS expression with doxycycline alone, or in the presence of 9 to 30 micromolar compound. (Dox+) represents control cells, showing GFP fluorescence at the plasma membrane, indicating KRAS attachment to the membrane. Treatment with 1-0175 has a dose-dependent effect on KRAS4b G12D localization at the plasma membrane. FIG. 4 depicts confocal images of the effect of compound 1-0176 on HeLa cells expressing eGFP-KRAS4b G12D in a doxycycline- inducible system.
Example 1-14: Mouse Xenograft Experiments
[0365] Human pancreas or lung adenocarcinoma cell lines are obtained from the American Type Culture Collection and cultured according to the cell supplier’s protocol, for a maximum of four passages before use. Cells are harvested at 70-80% confluence, washed with phosphate buffered saline, suspended in phosphate buffered saline, and implanted subcutaneously at 5 x 106 cells/0.2 mL into NCr nu/nu athymic mice, obtained from Charles River. Frederick National Laboratory for Cancer Research is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care is provided in accordance with the procedures outlined in the“Guide for Care and Use of Laboratory Animals” (National Research Council, 1996; National Academy Press, Washington, DC). When the tumors reach approximately 3 mm x 3 mm, the mice are distributed randomly into groups of 12 for treatment.
[0366] Compounds are injected into the tail veins of the mice, at 100 pmol/kg body weight, 3 times per week for 4 weeks. Control groups are treated with saline. Mice are weighed, and tumors are measured 2 times per week. Tumor volumes in mm3 are estimated by the formula (p/2 x length c width2). Mice are euthanized almost immediately after the last treatment. Blood is collected under isoflurane anesthesia. Tumors are removed and frozen immediately for biochemical analysis.
Example II- 1: General synthesis of 3-vinyl sulfonamide analogs
Figure imgf000260_0001
[0367] Provided above is a general synthesis that was used to produce various 3-vinyl sulfonamide compounds described herein. Conditions: (a) 2-chloroethanesulfonyl chloride, EtsN, DCM, 0°C - RT, 18 h; (b) TFA, DCM, 0°C - RT, 1 h; (c) R-C(0)Cl, EtsN, DCM, RT, 2 h or R-S(0)2Cl, EtsN, DCM, RT 2h. In step (c), R is Aryl (Ar).
Example II-2: Synthesis of (R)-N-(pyrrolidin-2-ylmethyl)ethenesulfonamide
Figure imgf000260_0002
[0368] The above compound 4 can be treated with various acid chlorides and sulfonyl chlorides under the conditions described in Example II- 1 to produce various 2-vinyl sulfonamide compounds described herein.
Example II-3: General scheme for (R)-2-(4-((3-(vinylsulfonamidomethyl)pyrrolidin-l- yl)sulfonyl)phenyl)acetamide analogs
Figure imgf000261_0001
[0369] To a solution of (R)-2-(4-((3-(vinylsulfonamidomethyl)pyrrolidin-l- yl)sulfonyl)phenyl)acetic acid (80 mg, 0.196 mmol), amine (3.76 mg, 0.235 mmol) and Hunig's Base (103 mΐ, 0.587 mmol) in DMF (500 pL) was added a solution of HATU (89 mg, 0.235 mmol) in DMF (500 pL) at rt. The plate was placed in the agitator overnight. The reaction mixtures were filtered and purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, phenomenex evo kinetex Prep-Cl8, 5 pm, 21x50 mm column, 2-10% MeCN in Water) to afford the desired product.
[0370] Various 2- and 3-substituted analogs were synthesized generally following the synthetic route shown above, including X-0000749, X-0000750, X-0000751, X-0000752, X- 0000753, X-0000754, X-0000755, X-0000763, X-0000774, X-0000775, X-0000776, X- 0000777, X-0000778, X-0000781, X-0000953, X-0000951, X-0000802, X-0000803, 1-0176, X-0000804, X-0000805, X-0000816, X-0000817, X-0000952, X-0000818, X-0000820, X- 0001010, C-0001094, C-0001032, C-0001034, C-0001098, C-0001025, C-0001040, X- 0001041, X-0001105, and X-0001103
Example II-4: General scheme for synthesis of various alkyl branched analogs
Figure imgf000261_0002
[0371] Various 2-substituted and 3-substituted branched analogs were synthesized generally following the procedure for X-0001302, shown above and described below. These analogs include X-0001131, X-0001132, X-0001133, X-0001289, X-0001290, X-0001291, C-0001348, C-0001305, C-0001424, C-0001425, C-0001426, C-0001360, C-0001359, X- 0001358, C-0001423, C-0001365, C-0001364, C-0001436, C-0001443, C-0001427, X- 0001361, C-0001618, C-0001362, C-0001363, C-0001393, C-0001427, C-0001394, X- 0001439, C-0001440, C-0001494, C-0001520, C-0001521, C-0001526, C-0001527, X- 0001546, C-0001545, C-0001468, C-0001527, C-0001470, C-0001529, C-0001582, X- 0001583, C-0001575, C-0001576, X-0001352, X-0001304, and X-0001430.
[0372] Synthesis of methyl (R)-2-(4-((2-((((henzyloxy)carhonyl)amino)methyl)pyrrolidin-l- yl)sulfonyl)phenyl)acetate: To a stirred solution of benzyl (R)-(pyrrolidin-2- ylmethyl)carbamate HC1 salt (0.85 g, 3.14 mmol) and triethylamine (2.26 mL, 15.71 mmol) in tetrahydrofuran (10 mL) at 0°C was added methyl 2-(4-(chlorosulfonyl)phenyl)acetate (1.16 g, 4.71 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 30 % ethyl acetate in hexane as eluent to give the title compound as gummy material m/z = 447.2 [M + H]+; Yield (0.84 g, 60 %).
[0373] Synthesis of methyl (R, Z)-2-( 4-( ( 2-( ( ((henzyloxyjcarhonyljaminojmelhyljpyrrolidin- l-yl)sulfonyl)phenyl)-3-phenylacrylate: To a stirred solution of methyl (R)-2-(4-((2- ((((benzyloxy)carbonyl)amino)methyl)pyrrolidin-l-yl)sulfonyl)phenyl)acetate (0.84 g, 1.88 mmol) in toluene (10 mL) in a sealed tube was added benzaldehyde (1.9 mL, 18.18 mmol), piperidine (2.4 mL, 18.18 mmol) and acetic acid (0.5 mL) and the sealed tube was closed and was stirred at 100 °C for 15 h . The reaction mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography using combiflash purifier with 20 % ethyl acetate in hexane as eluent to give the title compound as yellow liquid m/z = 535.2 [M + H]+; Yield (0.58 g, 58 %). [0374] Synthesis of methyl 2-(4-( ( (R)-2-(aminomethyl)pyrrolidin-l-yl)sulfonyl)phenyl)-3- phenylpropanoate: To a stirred solution of methyl (R,Z)-2-(4-((2-((((benzyloxy)carbonyl) amino)methyl)pyrrolidin-l-yl)sulfonyl)phenyl)-3-phenylacrylate (0.35 g, 0.65 mmol) in ethyl acetate (10 mL) was added palladium on carbon (0.05 g, 10 % wt) and the reaction mixture was stirred at room temperature under hydrogen bladder pressure for 15 h. The reaction mixture was filtered through Celite ® and the filtrate is evaporated under reduced pressure to give the title compound as gummy material m/z = 403.3 [M + H]+; Yield (0.25 g, crude).
[0375] Synthesis of methyl 3-phenyl-2-(4-( ( dl)-2-( vinylsulfonamidomelhyljpyrrolidin- 1 - yl)sulfonyl)phenyl)propanoate : To a stirred solution of methyl 2-(4-(((R)-2- (aminomethyl)pyrrolidin-l-yl)sulfonyl)phenyl)-3-phenylpropanoate (0.25 g, 0.62 mmol), and triethylamine (0.43 mL, 3.1 mmol) in tetrahydrofuran (10 mL) at 0 °C was added 2- chloroethane-l-sulfonyl chloride (0.13 mL, 1.24 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (25 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as brown liquid m/z = 493.2 [M + H]+; Yield (0.29 g, crude).
[0376] Synthesis of 3-phenyl-2-(4-( ( { R)-2-( vinylsulfonamidomethyl)pyrrolidin-l- yl)sulfonyl)phenyl)propanoic acid: To a stirred solution of methyl 3-phenyl-2-(4-(((R)-2- (vinylsulfonamidomethyl)pyrrolidin-l-yl)sulfonyl)phenyl)propanoate (0.29 g, 0.58 mmol) in tetrahydrofuran (5 mL) and water (5 mL) at 0°C was added lithium hydroxide monohydrate (0.24 g, 5.8 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction was cooled and evaporated under reduced pressure. The residue was diluted with cold water (25 mL) and acidified to pH~3 using saturated citric acid solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as yellow gum. m/z = 479.1 [M + H]+; Yield (0.22 g, crude).
[0377] Synthesis ofN-((( 2R)-l-( (4-(l -oxo- 3 -phenyl- 1 -(piper idin-l-yl)pr opan-2- yl)phenyl)sulfonyl)pyrrolidin-2-yl)me thy l)ethene sulfonamide (X-0001302): To a stirred solution of 3-phenyl-2-(4-(((R)-2-(vinylsulfonamidomethyl)pyrrolidin-l- yl)sulfonyl)phenyl)propanoic acid (0.22 g, 0.46 mmol), piperidine (0.05 g, 0.46 mmol) and triethylamine (0.33 mL, 2.3 mmol) in dichloromethane (5 mL) at 0 °C was added T3P (0.44 mL, 0.69 mmol, 50 % solution in ethyl acetate) and the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC using Inertsil ODS 3 V (250mm x 4.6mm x 5mic) column with 0.1 % ammonia in water as mobile phase A and acetonitrile as mobile phase B to give the title compound as white solid. Yield (0.02 g, 8 %).
Example II-5: General scheme for synthesis of various aniline analogs
Figure imgf000264_0001
1 ) HCI / dioxane
amide cou ip| ling /
alkylation
Figure imgf000264_0004
Figure imgf000264_0003
Figure imgf000264_0002
[0378] The general synthetic route shown above was used to synthesized various aniline analogs such as C-0001208, X-0001223, X-0001224, and X-0001225.
Example II-6: General schemes for various benzylamine analogs
Figure imgf000265_0001
[0379] The general synthetic routes shown above were used to synthesized various benzylamine analogs such as X-0000979, X-000098, X-0000986, X-0001044, X-0001045, X-0001046, and X-0001047.
Example II-7: General scheme for urea-linked analogs
Figure imgf000265_0002
[0380] Both 2- and 3-substituted urea-linked analogs were synthesized generally following the procedure for X-0001396, shown above and described below, including compounds X- 0001472, X-0001432, X-0001428, and X-0001473. [0381] Synthesis of tert-butyl (R)-((l-((4-nitrophenyl)sulfonyl)pyrrolidin-2-yl)methyl) carbamate: To a stirred solution of tert-butyl (R)-(pyrrolidin-2-ylmethyl)carbamate (1.8 g, 9.02 mmol) and triethylamine (6.27 mL, 45.1 mmol) in tetrahydrofuran (30 mL) at 0 °C was added 4-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and the reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was washed with n-pentane (100 mL) to give the title compound as off white solid m/z = 286.1 [M + H]+; Yield (3.0 g, 86 %).
[0382] Synthesis of tert-butyl (R)-((l-(( 4-aminophenyl)sulfonyl)pyrrolidin-2- yl)methyl)carbamate : To a stirred solution of tert-butyl (R)-((l-((4- nitrophenyl)sulfonyl)pyrrolidin-2-yl)methyl)carbamate (3.0 g, 7.78 mmol) in THF (30 mL) was added palladium on carbon (0.3 g, 10 % w/w) at room temperature and the reaction mixture was hydrogenated under hydrogen bladder for 12 h. The reaction mixture was filtered through Celite® bed and washed with THF (30 mL). The filtrate was evaporated under reduced pressure to get the title compound as gummy compound m/z = 356.0 [M + H] +; Yield (2.70 g, crude).
[0383] Synthesis of tert-butyl (R)-((l-((4-((4-(trifluoromethyl)benzyl)amino)
phenyl) sulfonyl)pyrrolidin-2-yl)methyl) carbamate: To a stirred solution of tert-butyl (R)-((l- ((4-aminophenyl)sulfonyl)pyrrolidin-2-yl)methyl)carbamate (2.0 g, 5.62 mmol) in 1,2 dichloroethane (30 mL) at 0°C were added 4-(trifluoromethyl)benzaldehyde (1.17 g, 6.74 mmol) and acetic acid (2.0 mL). The reaction mixture was stirred at room temperature for 5h and then cooled to 0 °C, sodium triacetoxyborohydride (2.38 g, 11.24 mmol) was added and stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 40 % ethyl acetate in hexane as eluent to give the title compound as white solid m/z = 514.4 [M + H]+; Yield (1.8 g, 78 %).
[0384] Synthesis of tert-butyl (R)-((l-((4-(3-isopropyl-l-(4-(trifluoromethyl)benzyl) ureido)phenyl)sulfonyl)pyrrolidin-2-yl)methyl) carbamate: To a stirred solution of tert-butyl (R)-((l-((4-((4-(trifluoromethyl)benzyl)amino)phenyl)sulfonyl)pyrrolidin-2- yl)methyl)carbamate (0.7 g, 1.36 mmol) in dichloromethane (15 mL) at 0 °C were added triphosgene (0.6 g, 2.02 mmol) and N, N-diisopropylethylamine (1.2 mL, 6.8 mmol) and the reaction mixture was stirred at 0 °C for 0.5 h, and then isopropyl amine (0.133 mL, 1.63 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 80 % ethyl acetate in hexane as eluent to give the title compound as gummy compound m/z = 499.3 [M + H]+; Yield (0.6 g, 74 %).
[0385] Synthesis of (R)-l-(4-((2-(aminomethyl)pyrrolidin-l-yl)sulfonyl)phenyl)-3- isopropyl-l-(4-(trifluoromethyl)henzyl)urea HCl salt. To a stirred solution of tert-butyl (R)- ((l-((4-(3-isopropyl-l-(4-(trifluoromethyl)benzyl)ureido)phenyl)sulfonyl)pyrrolidin-2- yl)methyl)carbamate (0.1 g, 0.167 mmol) in dichloromethane (5 mL) at 0 °C was added hydrochloric acid (1.0 mL, 4N in dioxane) drop wise and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and dried to get the title compound as white solid m/z = 499.3 [M + H] +; Yield (0.09 g, crude).
[0386] Synthesis of (R)-N-( f-(( 4-(3-isopropyl-l-( 4-(trifluoromethyl) benzyl)
ureido)phenyl)sulfonyl)pyrrolidin-2-yl)methyl)ethene sulfonamide (X-0001396): To a stirred solution of (R)- 1 -(4-((2-(aminomethyl)pyrrolidin- 1 -yl)sulfonyl)phenyl)-3 -isopropyl- 1 -(4- (trifluoromethyl)benzyl)urea HCl salt (0.09 g, 0.168 mmol) and triethylamine (0.12 mL, 0.84 mmol) in dichloromethane (5 mL) at 0 °C was added ethenesulfonyl chloride (0.026 g, 0.21 mmol) and the reaction mixture was stirred at 0 °C for 0.5h and then at room temperature for 0.5 h. The reaction mixture was evaporated under reduced pressure. The crude product was purified by preparative HPLC using Kinetex C18 (lOOmm X 4.6 mm X 2.6pm) column with 0.1 % trifluoroacetic acid in water as mobile phase A and acetonitrile as mobile phase B to give the title compound as white solid. Yield (0.15 g, 15 %). Example II-8: Synthesis of N-(((3S)-l-(l-(piperidin-3-ylmethyl)-2-((4- (trifluoromethyl)benzyl)amino)-lH-benzo[d]imidazole-5-carbonyl)pyrrolidin-3- yl)methyl)ethenesulfonamide hydrochloride (HCI salt of X-0001002)
Figure imgf000268_0001
[0387] Synthesis of tert-butyl 3-( ( ( 4-(methoxycarbonyl)-2-nitrophenyl)amino)methyl) piperidine-l-carboxylate: To a stirred solution of l-fluoro-2-nitrobenzene (0.1 g, 0.52 mmol) in N,N-dimethyformamide (5 mL) at room temperature was added potassium carbonate (0.14 g, 1.04 mmol) and tert-butyl 3-(aminomethyl)piperidine-l-carboxylate (0.13 g, 0.62 mmol), the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 20 % ethyl acetate in hexane as eluent to give the title compound as yellow solid m/z = 392.1 [M + H] ; Yield (0.15 g, 73 %).
[0388] Synthesis tert-butyl 3-(((2-amino-4-(methoxycarbonyl)phenyl)amino)methyl) piperidine-l-carboxylate: To a stirred solution of tert-butyl 3 -(((4-(m ethoxy carbonyl)-2- nitrophenyl)amino)methyl)piperidine-l-carboxylate (1.4 g, 3.56 mmol) in methanol (20 mL) was added palladium on carbon (0.5 g, 10 % wt) and the reaction mixture was stirred under hydrogen atmosphere at room temperature for 6 h. The reaction mixture was filtered through Celite® and washed with methanol, the combined filtrate was evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 5 % methanol in dichloromethane as eluent to give the title compound as pale yellow liquid m/z = 364.2 [M + H]+; Yield (1.1 g, 85 %). [0389] Synthesis of methyl 2-amino- 1-( (l-( tert-butoxycarbonyl)piperidin-3-yl)methyl)-lH- benzo[d]imidazole-5-carboxylate: To a stirred solution of tert-butyl 3-(((2-amino-4- (methoxy carbonyl)phenyl)amino)methyl)piperi dine- l-carboxylate (1.1 g, 3.03 mmol) in acetonitrile (10 mL) and water (3 mL) at 0°C was added cyanogen bromide (0.34 g, 3.33 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 5 % methanol in dichloromethane as eluent to give the title compound as green liquid m/z = 389.1 [M + H]+; Yield (0.8 g, 68 %).
[0390] Synthesis of methyl l-((l-(tert-butoxycarbonyl)piperidin-3-yl)methyl)-2-((4- (trifluoromethyl)benzyl)amino)-lH-benzo[d]imidazole-5-carboxylate: To a stirred solution of methyl 2-amino-l-((l-(tert-butoxycarbonyl)piperidin-3-yl)methyl)-lH-benzo[d]imidazole- 5-carboxylate (0.8 g, 2.06 mmol) and 4-(trifluoromethyl)benzaldehyde (0.43 g, 2.47 mmol) in toluene (30 mL) was heated at l30°C under dean-stark condenser for 16 h and the solvent was evaporated, the resulting mixture was cooled to 0°C and was added methanol (20 mL) and sodium borohydride (0.12 g, 5.15 mmol) portion wise and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was quenched with water (20 mL) and evaporated the methanol solvent under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 5 % methanol in dichloromethane as eluent to give the title compound as off white solid m/z = 547.2 [M + H]+; Yield (0.3 g, 26 %).
[0391] Synthesis of l-((l-(tert-butoxycarbonyl)piperidin-3-yl)methyl)-2-((4- (trifluoromethyl)benzyl)amino)-lH-benzo[d]imidazole-5-carboxylic acid: To a stirred solution of methyl l-((l-(tert-butoxycarbonyl)piperidin-3-yl)methyl)-2-((4- (trifluoromethyl)benzyl)amino)-lH-benzo[d]imidazole-5-carboxylate (0.3 g, 5.49 mmol) and in methanol (5 mL), tetrahydrofuran (5 mL) water (2.5 mL) at 0 °C was added lithium hydroxide monohydrate (0.4 g, 54.94 mmol) and the reaction mixture stirred at 50 °C for 4 h. The reaction mixture was cooled, diluted with water (20 mL) and evaporated under reduced pressure. The residue was diluted with water, acidified to pH~3 using 1N hydrochloric acid and was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as green solid m/z = 533.2 [M + H]+; Yield (0.28 g, crude).
[0392] Synthesis of tert-hutyl 3-((2-((4-(trifluoromethyl)benzyl)amino)-5-((S)-3- (vinylsulfonamidomethyl)pyrrolidine-l-carbonyl)-lH-benzo[d]imidazol-l- yl)methyl)piperidine-l-carboxylate: To a stirred solution of l-((l-(tert- butoxycarbonyl)piperidin-3-yl)methyl)-2-((4-(trifluoromethyl)benzyl)amino)-lH- benzo[d]imidazole-5-carboxylic acid (0.28 g, 0.52 mmol) and N-(((3 S)-l -(2,2,2- trifluoroacetyl)-H4-pyrrolidin-3-yl)methyl)ethenesulfonamide (0.22 g, 0.78 mmol) in tetrahydrofuran (15 mL) at 0°C was added triethylamine (0.37 mL, 2.63 mmol) and HATU (0.19 g, 0.52 mmol) and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC using 0.1 % ammonia in water as mobile phase A and acetonitrile as mobile phase B to give the title compound as green solid m/z = 705.2 [M + H]+; Yield (0.14 g, 72 %).
[0393] Synthesis ofN-(((3S)-l-(l-(piperidin-3-ylmethyl)-2-((4-
(trifluoromethyl)benzyl)amino)-lH-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)methyl) ethene sulfonamide hydrochloride (HCl salt ofX-0001002 ): To a stirred solution of tert-butyl 3-((2-((4-(trifluoromethyl)benzyl)amino)-5-((S)-3-(vinylsulfonamidomethyl) pyrrolidine- 1- carbonyl)-lH-benzo[d]imidazol-l-yl)methyl)piperidine-l-carboxylate (0.14 g, 0.232 mmol) in dichloromethane (10 mL) at 0 °C was added 4N HCl in dioxane (0.4 mL) and the reaction mixture stirred at room temperature for 2 h. The reaction mixture evaporated under reduced pressure to give the title compound as off white gummy liquid. Yield (0.1 g, 85 %). Example II-9: Synthesis of (X)-N-((l-(l-methyl-3-(piperidin-4-yl)-lH-indole-5-carbonyl) pyrrolidin-3-yl) methyl) ethenesulfonamide hydrochloride (HC1 salt of X-0001064):
Figure imgf000271_0001
[0394] In addition to compound X-0001064, compounds C-0001067, C-0001068, X- 0001115, X-0001171, X-0001172, X-0001253, X-0001256, X-0001257, X-0001121, and X- 0001119 were also synthesized generally following the scheme above and procedures described below.
[0395] Synthesis of 3-( l -(tert-butoxycarbonyl)-l , 2, 3, 6-tetrahydropyridin-4-yl)-lH-indole- 5-carboxylic acid: To a stirred solution of methyl lH-indole-5-carboxylate (2.0 g, 11.40 mmol) in methanol (20 mL) were added potassium hydroxide (1.5 g, 34.2 mmol) and tert- butyl 4-oxopiperidine-l-carboxylate (4.5 g, 22.8 mmol) at room temperature and the mixture was heated to reflux for l6h. After completion of the reaction, concentrated and diluted with water (20 mL) and acidified using citric acid solution (10 mL, /;H~6) The obtained solid was filtered and dried giving the title compound as a pale yellow solid m/z = 341.3 [M - H]+; Yield (1.7 g, 43%).
[0396] Synthesis of methyl 3-( l -( tert-butoxycarbonyl)-l , 2, 3, 6-tetrahydropyridin-4-yl)-lH- indole-5-carboxylate To a stirred solution of 3 -(l-(tert-butoxy carbonyl)- 1, 2,3,6- tetrahydropyridin-4-yl)-lH-indole-5-carboxylic acid (1.5 g, 4.38 mmol) in N,N- Dimethylformamide (15 mL) were added potassium carbonate (1.2 g, 8.77 mmol) and methyl iodide (0.4 mL, 6.57 mmol) at 0°C and allowed to stir at room temperature for 2h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic layer was washed with water (60 mL), brine (60 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 20% ethyl acetate in hexane as an eluent to give title compound as off white solid m/z = 355.2 [M - H]+ ; Yield (0.7 g, 47%). [0397] Synthesis of methyl 3-( l -( tert-butoxycarbonyl)-l, 2, 3, 6-tetrahydropyridin-4-yl)-l - methyl-lH-indole-5-carboxylate: To a stirred solution of methyl 3 -(1 -(tert-butoxy carbonyl)- l,2,3,6-tetrahydropyridin-4-yl)-lH-indole-5-carboxylate (0.5 g, 1.40 mmol) in
tetrahydrofuran (10 mL) was added 60% sodium hydride (67 mg, 1.68 mmol) and methyl iodide (0.1 mL, 2.1 mmol) at 0 °C and left it to stir at room temperature for 3h. It was quenched with water (10 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title compound as an off white solid. ¾ NMR (400 MHz, CDCb): d ppm 8.61 (s, 1H), 7.95 (dd, J= 8.8, 1.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.20 (s, 1H), 4.15 (d, j= 8.2 Hz, 2H), 3.94 (s, 3H),
3.79 (s, 3H), 3.68 (t, j = 11.2 Hz, 2H), 2.55 (s, 2H), 1.50 (s, 9H): Yield (0.35 g, 67%).
[0398] Synthesis of methyl 3-(l-(tert-butoxy carbonyl) piperidin-4-yl)-l -methyl- lH-indole- 5-carboxylate: To a stirred solution of methyl 3-(l-(tert-butoxycarbonyl)-l,2,3,6- tetrahydropyridin-4-yl)-l -methyl- lH-indole-5-carboxylate (0.7 g, 1.89 mmol) in
tetrahydrofuran (15 mL) was added 10% Palladium on carbon (0.2 g) at room temperature and stirred the mixture under hydrogen balloon pressure for 3 h. The reaction mixture was filtered through a celite bed, washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to give the title compound as an off white solid m/z = 373.2 [M + H]+; Yield (0.55 g, 78%).
[0399] Synthesis of 3-(l-( tert-butoxy carbonyl) piperidin-4-yl)-l -methyl- lH-indole-5- carboxylic acid: To a solution of methyl 3 -(1 -(tert-butoxy carbonyl) piperidin-4-yl)-l- m ethyl -///-indole-5-carboxylate (0.55 g, 1.47 mmol) in (1 : 1 : 1) tetrahydrofuran, methanol and water (9 mL) solvent mixture was added lithium hydroxide monohydrate (0.5 g, 11.82 mmol) at 0 °C. The mixture was stirred at room temperature for 20 h. After completion of the reaction, concentrated under reduced pressure to dryness. It was then diluted with water (5 mL) and acidified using citric acid solution (3 mL, /;H~6) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title compound as an off white solid m/z = 357.1 [M - H]+; Yield (0.32 g, 61%).
[0400] Synthesis of (S)-tert-butyl 4-(l-methyl-5-(3-(vinylsulfonamidomethyl) pyrrolidine- 1- carbonyl)-lH-indol-3-yl) piperidine- 1-carboxylate: To a stirred solution of 3-(l-(tert- butoxycarbonyl)piperidin-4-yl)-l -methyl- lH-indole-5-carboxylic acid (0.22 g, 0.614 mmol) in /V, /V-di m ethyl form am i de (5 mL) at 0 °C were added (S)-N-( pyrrol idin-3- ylmethyl)ethenesulfonamide (0.23 g, 1.22 mmol), l-[Bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate (0.46g, 1.22 mmol) and /V- Ethyldiisopropylamine (0.25 mL, 1.53 mmol) at 0 °C and allowed to stir at room temperature for 4h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified over silica gel (60-120) using 10 % methanol in ethyl acetate as an eluent to afford the title compound as a colorless semi solid m/z = 531.2 [M + H]+; Yield (0.25 g, 78%).
[0401] Synthesis of (S)-N-((l-(l-methyl-3-(piperidin-4-yl)-lH-indole-5-carbonyl) pyrroIidin-3-yI) methyl) ethene sulfonamide hydrochloride (HCl salt of X-0001064) : To a stirred solution of /c/V-butyl (S)-4-(l-methyl-5-(3-(vinylsulfonamidomethyl) pyrrolidine- 1- carbonyl)-lH-indol-3-yl) piperidine- l-carboxylate (0.1 g, 0.188 mmol) in l,4-dioxane (2 mL) at 0 °C was added 4M HCl in l,4-dioxane (0.2 mL) drop wise and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to dryness. The crude product was triturated with diethyl ether to give the title compound as an off white solid. Yield (0.042 g, 48 %).
Example 11-10: ((R)-N,N-dimethyl-l-(4-(trifluoromethyl)benzyl)-5-((2- (vinylsulfonamidomethyl)pyrrolidin-l-yl)sulfonyl)-lH-indazole-3-carboxamide (X-
Figure imgf000273_0001
[0402] In addition to X-0001433, compound X-0001434 was also synthesized generally following the scheme above, and procedure described below. [0403] Synthesis of 5-bromo-lH-indazole-3-carboxylic acid: A suspension of indazole-3- carboxylic acid (5.0 g, 30.8 mmol) in glacial acetic acid (250 mL) was heated at 120° C to get a clear solution. The solution was cooled to 90 °C and added a solution of bromine (3.17 mL, 61.7 mmol) in glacial acetic acid (50 mL) drop wise and the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature, poured into ice water, the precipitated solid was filtered, washed with water and n-pentane and dried in high vacuum to give the title compound as off white solid m/z 241.0 [M + H]+ ; Yield (6 g, 81%).
[0404] Synthesis of 5-bromo-N,N-dimethyl-lH-indazole-3-carboxamide: A stirred solution of 5-bromo-lH-indazole-3-carboxylic acid (2 g, 8.33 mmol) and I,G-carbonyldiimidazol (2.02 g, 12.4 mmol) in N,N-Dimethylformamide (20 mL) was heated at 45 °C for 1 h. The reaction mixture was cooled to room temperature and added dimethyl amine (8.33 mL, 20.8 mmol, 2M in tetrahydrofuran) drop wise and the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layer was washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as off white solid m/z 270.0 [M + H]+ ; Yield (1.3 g, 58 %).
[0405] Synthesis of 5-bromo-N,N-dimethyl-l-(4-(trifluoromethyl)benzyl)-lH-indazole-3- carboxamide: To a stirred 5-bromo-N,N-dimethyl-lH-indazole-3-carboxamide (1.5 g, 5.6lmmol) in DMF (20 mL) was added potassium carbonate (1.54 g, 11.22 mmol) and 1- (bromomethyl)-4-(trifluoromethyl)benzene (1.6 g, 6.74 mmol) and stirred at room
temperature for 4 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash chromatography using combiflash purifier with 28 % ethyl acetate in hexane as eluent to give the title compound as off white solid m/z 425.9 [M + H]+; Yield (2.0 g, 84 %).
[0406] Synthesis of 2-ethylhexyl 3-((3-(dimethylcarbamoyl)-l-(4-(trifluoromethyl)benzyl)~ lH-indazol-5-yl)thio)propanoate: To a stirred solution of 5-bromo-N,N-dimethyl-l-(4- (trifluoromethyl)benzyl)-lH-indazole-3-carboxamide (2.0 g, 4.7 mmol) and 2-ethylhexyl 3- mercaptopropanoate (2.05 g, 9.41 mmol) in dioxane (50 mL) in a sealed tube was added diisopropylethylamine (2.5 mL, 14.1 mmol) and xanthphos (0.136 g, 0.23 mmol), then reaction mixture was degassed with nitrogen for 5 min, added Pd2(dba)3 (0.215 g, 0.23 mmol) and the sealed tube was closed and was stirred at 100 °C for 15 h . The reaction mixture was cooled, filtered through Celite® and the filtrate was diluted with water and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography using combiflash purifier with 35 % ethyl acetate in hexane as eluent to give the title compound Yellow liquid m/z 564.3 [M + H]+; Yield (2.5 g, 94 %).
[0407] Synthesis of 5-mercapto-N,N-dimethyl-l-( 4-( trifluoromethyl)benzyl)-lH-indazole-3- carboxamide: To a stirred solution of 2-ethylhexyl 3-((3-(dimethylcarbamoyl)-l-(4- (trifluoromethyl)benzyl)-lH-indazol-5-yl)thio)propanoate (2.5 g, 4.4 mmol) in
tetrahydrofuran (30 mL) at 0 °C was added sodium ethoxide (2.85 mL, 8.8 mmol, 21 % solution in ethanol) and the reaction mixture was stirred at room temperature 4 h . The reaction mixture was quenched with 1 N hydrochloric acid (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography using combiflash purifier with 40 % ethyl acetate in hexane as eluent to give the title compound as yellow solid m/z 380.1 [M + H]+. Yield (1.5 g, 89 %).
[0408] Synthesis of 3-(dimethylcarbamoyl)-l-(4-(trifluoromethyl)benzyl)-lH-indazole-5- sulfonyl chloride: To a stirred solution of 5-mercapto-N,N-dimethyl-l-(4- (trifluoromethyl)benzyl)-lH-indazole-3-carboxamide (0.40 g, 1.0 mmol) in acetonitrile (10 mL) was added hydrogen peroxide (0.6 mL, 5.27 mmol, 30 % solution) and the reaction mixture was cooled to 0 °C. Then thionyl chloride (0.35 mL, 4.22 mmol) was added drop wise and the reaction mixture was stirred at room temperature 2 h. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as white solid m/z 446.1 [M + H]+. Yield (0.3 g, crude).
Synthesis of ((R)-N,N-dimethyl-l-(4-(trifluoromethyl)benzyl)-5-((2-
(vinylsulfonamidomethyl)pyrrolidin-l-yl)sulfonyl)-lH-indazole-3 -carboxamide (X-0001433): To a stirred solution of (R)-N-(pyrrolidin-2-ylmethyl)ethenesulfonamide (0.130 g, 0.67 mmol) and triethylamine (0.188 mL, 1.34 mmol) in tetrahydrofuran (5 mL) at 0 °C was added 3-(dimethylcarbamoyl)-l-(4-(trifluoromethyl)benzyl)-lH-indazole-5-sulfonyl chloride (0.20 g, 0.44 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound as white solid. Yield (0.080 g, 26 %).
Example 11-11: Synthesis of X-0001495
Figure imgf000276_0001
[0409] Synthesis of sodium 2-chloroprop-2-ene-l -sulfonate: To a stirred solution of sodium sulfite (5.7 g, 26.31 mmol) in water (35 ml) was dropwise added 2,3-dichloroprop-l-ene (5.0 g, 26.31 mmol) and the reaction mixture was stirred at 120 °C for 3h. The reaction mixture was evaporated under reduced pressure, the resulting crude was diluted with ethanol (45 mL) and the reaction mixture was refluxed for 30 min. The reaction mixture was filtered and filtrate was cooled. The crystalline solid precipitated was collected by filtration as white solid. ¾ NMR (400 MHz, DMSO de) d 5.44 (s, 1H), 5.27 (s, 1H), 3.42 (s, 2H); Yield (4g, crude).
[0410] Synthesis of 2-chloroprop-2-ene-l-sulfonyl chloride: A mixture of sodium 2- chloroprop-2-ene-l -sulfonate (0.7 g, 40.00 mmol) and phosphorous pentachloride (0.8 g, 40.00 mmol) was stirred vigorously at 120 °C in sealed tube for 30 min. The reaction mixture was cooled and diluted with dichloromethane (50 mL). The organic phase was washed with 5% sodium bicarbonate solution (2 x 25 mL), water (35 mL), dried over anhydrous sodium sulphate and evaporated under reduced pressure to give the title compound as brown liquid. ¾ NMR (400 MHz, DMSO de) d 5.44 (s, 1H), 5.29 (s, 1H), 3.45 (s, 2H). Yield (0.5 g, crude).
[0411] Synthesis of (R)-2-(4-((2-(((2-chloroallyl)sulfonamido)methyl)pyrrolidin-l- yl)sulfonyl)-3-fluorophenyl)-N-(4-(trifluoromethyl)benzyl)acetamide: To a stirred solution of (R)-2-(4-((2-(aminomethyl)pyrrolidin-l-yl)sulfonyl)-3-fluorophenyl)-N-(4- (trifluoromethyl)benzyl)acetamide (0.4 g, 0.845 mmol) in dichloromethane (15 mL) at 0 °C was added triethylamine (0.48 mL, 3.382 mmol) and 2-chloroprop-2-ene-l-sulfonyl chloride (0.17 g, 1.014 mmol) and the reaction mixture was stirred at room temperature for lh. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 70 % ethyl acetate in hexane as eluent to give the title compound as yellow solid m/z = 574 [M + H]+; Yield (0.12 g, crude)
[0412] Synthesis of (R)-2-(3-fluoro-4-((2-((propa-l,2-dien-l-ylsulfonamido)
methyl)pyrrolidin-l-yl)sulfonyl)phenyl)-N-(4-(trifluoromethyl)henzyl)acetamide (X- 0001495): To a stirred solution of (R)-2-(4-((2-(((2-chloroallyl)sulfonamido)methyl) pyrrolidin-l-yl)sulfonyl)-3-fluorophenyl)-N-(4-(trifluoromethyl)benzyl)acetamide (0.1 g,
0.16 mmol) in dichloromethane (10 mL) was added triethylamine (0.11 mL, 0.81 mmol) and the reaction mixture was stirred at room temperature for lh. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC using BEH C18 (50 mm x 2.1 mm x 1.7 mic) column with 0.1 % formic acid in water and acetonitrile as mobile phase to give the title compound as off white solid.
Example 11-12: Synthesis of X-0001554
Figure imgf000277_0001
[0413] Synthesis of (R)-2-(4-((2-((l, l-dioxidoisothiazol-2(3H)-yl)methyl)pyrrolidin-l- yl)sulfonyl)phenyl)-N-(4-(trifluoromethyl)benzyl)acetamide To a stirred solution of (R)-2-(4- ((2-(((2-chloroallyl)sulfonamido)methyl)pyrrolidin-l-yl)sulfonyl)phenyl)-N-(4- (trifluoromethyl)benzyl)acetamide (0.1 g, 0.41 mmol) in acetonitrile (10 mL) was added cesium carbonate (0.11 g, 0.33 mmol) and the reaction mixture was stirred at 80 °C for lh. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using combiflash purifier with 70 % ethyl acetate in hexane as eluent to give the title compound as off white solid.
Example 11-13: Synthesis of N-(4-(trifluoromethyl)benzyl)-2-(4-((3- (vinylsulfonamidomethyl)phenyl)sulfonyl)phenyl)acetamide (X-0001579)
Figure imgf000278_0001
[0414] Synthesis of tert-butyl (3-bromobenzyl)carbamate: To a stirred solution of (3- bromophenyl)methanamine hydrochloride (2.0 g, 0.089 mol) in dichloromethane was added triethylamine (1.39 mL, 0.010 mol) and stirred for 10 minutes. After 10 minutes Di-tert- butyldi carbonate (2.35 g, 0.010 mol) was added and stirred for 6h. The reaction mixture was diluted with water and extracted in to dichloromethane. The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by combiflash purifier with 18 % ethyl acetate in hexane as an eluent give the title compound as semi solid m/z = 187.9 [M + H]+; Yield: (2.2 g, 76 %). [0415] Synthesis of tert-butyl (3-((4-(2-oxo-2-((4-(trifluoromethyl)benzyl)amino) ethyl)phenyl)thio)benzyl)carbamate: To a stirred solution of 2-(4-mercaptophenyl)-N-(4- (trifluoromethyl)benzyl)acetamide (1.0 g, 3.07 mmol) and tert-butyl (3-bromobenzyl) carbamate (1.05 g, 3.69 mmol) in dioxane (15 mL) in a sealed tube was added
diisopropylethylamine (1.07 mL, 6.0 mmol), then reaction mixture was degassed with nitrogen for 5 min, then added xantphos (0.177 g, 0.307 mmol) and Pd2(dba)3 (0.14 g,0. l5 mmol) and the sealed tube was closed and was stirred at 100 °C for 6 h. The reaction mixture was cooled, filtered through Celite ® and the filtrate washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by combiflash purifier with 40 % ethyl acetate in hexane as an eluent give the title compound as yellow solid m/z = 430.9 [M + H]+; Yield: (0.65 g, 40 %)
[0416] Synthesis of tert-butyl (3-((4-(2-oxo-2-((4-(trifluoromethyl)benzyl) amino)ethyl) phenyl)sulfonyl)benzyl)carbamate To a stirred solution of tert-butyl (3-((4-(2-oxo-2-((4- (trifluoromethyl)benzyl)amino)ethyl)phenyl)thio)benzyl)carbamate (0.65 g, 1.2 mmol) in dichloromethane (10 mL) at 0 °C was added m-chloroperbenzoic acid (0.9 g, 3.67 mmol ) portion wise and the reaction mixture was stirred at room temperature for 5h. The reaction mixture was quenched with saturated sodium bicarbonate solution (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give title compound m/z = 506.8 [M + H]+; Yield: (0.35g, crude).
[0417] Synthesis of 2-(4-((3-(aminomethyl)phenyl)sulfonyl)phenyl)-N-(4-(trifluoromethyl) benzyl)acetamide hydrochloride : To a stirred solution of tert-butyl (3-((4-(2-oxo-2-((4- (trifluoromethyl)benzyl)amino)ethyl)phenyl)sulfonyl)benzyl)carbamate (0.35 g, 0.62 mmol) in dichloromethane (10 mL) at 0 °C was added 4M HC1 in dioxane (3mL) drop wise and the reaction mixture was stirred at room temperature for 6h. The reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and dried to get the title compound (0.2 g, crude) as semi solid m/z 462.9 [M + H]+
[0418] Synthesis of N-( 4-(trifluoromethyl)benzyl)-2-( 4-( (3-( vinylsulfonamidomethyl) phenyl) sulfonyl)phenyl)acetamide (X-0001579 ): To a stirred solution of 2-(4-((3- (aminomethyl)phenyl) sulfonyl)phenyl)-N-(4-(trifluoromethyl)benzyl)acetamide
hydrochloride (0.2 g, 0.4 mmol), triethylamine (0.l7mL, 1.2 mmol) in dichloromethane (5 mL) at 0 °C was added 2-chloroethane-l-sulfonyl chloride (0.08 mL, 8.0 mmol) and the reaction mixture was stirred at 0°C for 0.5 h and room temperature for 0.5h. The reaction mixture was evaporated under reduced pressure. The crude product was purified by preparative HPLC using X bridge (250mm X 4.6mm X 5mic) column with 0.1% Ammonia in water and acetonitrile as mobile phase to give the title compound as white solid. Yield (0.03 g, 14 %).
Example 11-14: Additional Compounds
[0419] Additional compounds synthesized using methods similar to those described in the above Examples are provided in Table II-1 below. Characterization of compounds is provided in Table II-2 below.
Table II-l. Additional synthesized compounds
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0002
Table II-2. Characterization of synthesized compounds
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0002
_
[0420] Compounds were evaluated using cell-based proliferation assays, using a mouse embryonic fibroblast (MEF) cell line panel generally following the procedure laid out in Example I- 10 above. Results of the evaluation are shown in Tables II-3 through II-6 below, as IC50 values.
Table II-3. Evaluation of selected compounds using cell-based proliferation assays (n=l; IC50 units are mM).
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Table II-4. Evaluation of selected compounds using cell-based proliferation assays. SD = standard deviation, (±); n = number of replicates; IC50 is average in mM.
Figure imgf000325_0001
Table II-5. Evaluation of selected compounds using cell-based proliferation assays. SD = standard deviation, (±); n = number of replicates; IC50 is average in mM.
Figure imgf000326_0001
Table II-6. Evaluation of selected compounds using cell-based proliferation assays. SD = standard deviation, (±); n = number of replicates; IC50 is average in mM.
Figure imgf000326_0002
[0421] A heat map comparing cell-based proliferation data across selected compounds is presented in FIG. 9, with a table summarizing the heat map data in FIG. 10.
[0422] Selected compounds were also evaluated for protein labeling using MALDI, generally following the procedure laid out in Example 1-9 above. Results are presented in Table II-7 below. Table II-7. Labeling of K-Ras4b(l-l88) GDP as evaluated by MALDI (20: 1, 24 h). SD = standard deviation, (±); n = number of replicates
Figure imgf000327_0001
Figure imgf000328_0001

Claims

CLAIMS What is claimed is:
1. A compound of F ormul a (X) :
Figure imgf000329_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rxl, Rx2, and Rx3 are independently hydrogen, -CN, or alkyl; or Rx2 and Rx3 together form alkenyl; or Rxl and Rx2 together with the carbon atoms to which they are attached form heteroaryl, heterocycloalkenyl, or cycloalkenyl; or Ral and Rx2 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 -ORx4, wherein each Rx4 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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0; Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein when A is phenyl, Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, cycloalkyl,
heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -S02Ral°; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently
unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2,
-NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, 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)-, Ral and one Ra4, together with the atoms to which they are attached, form a spirocycle with ring A, wherein the spirocycle is
unsubstituted or substituted with one or more halo;
each Ra5 is independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15,
wherein 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, -ORa16, =0, -NRal7Ral8,-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each
Figure imgf000331_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, Ra35, Ra54, and Ra55, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra23, -ORa24, and
-SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NH2, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, and Ra39 is independently hydrogen, alkyl, or haloalkyl;
wherein each alkyl or haloalkyl or Ra22 and Ra23 is independently
unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which 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 Ra40 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.
2. The compound of claim 1, wherein the compound is of Formula (X-I):
Figure imgf000333_0001
or a pharmaceutically acceptable salt thereof, wherein A is 4- to lO-membered heterocycloalkyl, and B, X, Rxl, Rx2, Rx3, Ral, R32, Ra3, Ra4, Ra5, m, and n are as defined for Formula (X).
3. The compound of claim 1 or 2, wherein the compound is of Formula (X-A):
Figure imgf000333_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, R^, Rx3, Ral, R32, Ra3, Ra4, Ra5, and n are as defined for Formula (X).
4. The compound of claim 1 or 2, wherein the compound is of Formula (X-C):
Figure imgf000333_0003
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Rxl, R52, Rx3, Ral, R32, Ra3, Ra4, Ra5, and n are as defined for Formula (X).
5. The compound of claim 1 or 2, wherein the compound is of Formula (X-B):
Figure imgf000334_0001
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-,— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0 wherein when Y is -CH2- and B is phenyl,
Figure imgf000334_0002
-C(Ra6)2-;
r is 0, 1, or 2;
p is an integer from 0 to 7;
and B, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (X).
6. The compound of claim 1, wherein the compound is of Formula (I):
Figure imgf000334_0003
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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, wherein when Ral is alkyl or haloalkyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(O)-;
Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -N02, -CN, -S02NH2, -NRa7Ra8, -ORa9, and -S02Ral°, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N02, -CN, -S02NH2, -NRa7Ra8, -ORa9, =0, -SRa47, and -S02Ral°, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Ra2 and one Ra4, 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 Ra3 and one Ra4, 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 Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -N02, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo,
-ORa16, =0, -NRal7Ra18,
-CN, -SFs, -SO2NRa50Ra51, -SRa52, -S02Ra53, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each
Figure imgf000336_0001
Ra50, Ra51, Ra52, Ra53, Ra54, Ra55, Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral6, Ral7, Ral8, Ral9, Ra20, R321, and Ra35, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -NRa22Ra2\
-ORa24, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NIL·, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Ra22, Ra23, Ra24, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13; and
n is an integer from 0 to 11.
7. The compound of claim 6, 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)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when A is piperidinyl and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-;
each Ra6 is independently hydrogen, halo, alkyl, or haloalkyl;
Ra46 is hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and =0;
Ral is hydrogen, alkyl, or cycloalkyl, wherein when Ral is alkyl, X is -S(O)-, -S(0)2- , -S(0)NRa46-, -C(S)-, or -C(O)-; Ra2 and Ra3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRa7Ra8, -ORa9, and -SCkR310, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Ra4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2,
-NRa7Ra8, -ORa9, =0, -SRa47, and -SCkR310, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Ra7, Ra8, Ra9, Ral°, and Ra47 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, or halocycloalkyl; or two to four Ra4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or Ra2 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ra3 and one Ra4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl; or Ral and Ra2, together with the atoms to which they are attached, form a
heterocycloalkyl; or Ra2 and Ra3, 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)NRa46-, or -C(S)-, Ral and one Ra4, together with the atoms to which they are attached, form a heterocycloalkyl; each Ra5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRa48Ra49, -NRallRa12, -ORa13, -S02Ral4, =0, and -SRa15, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa16, =0, -NRal7Ra18, -CN, -SFs, -SO2NRa50Ra51, -SRa52, -SCkR353, and Ra35, wherein each Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each aryl, heteroaryl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -SFs, and Ra35, wherein Ra35 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORa19, =0, -NRa20Ra21, -CN, -SFs, -S02NRa54Ra55, -SRa56,
-S02Ra57, and Ra58, wherein each Ra58 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Ral4 Ra33 Ral6 pa I 7 pa I X pa4X Ra49 paSO RaS I Ra52 pa53 pa54 RaSS
Ra56, and Ra57 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
each Ral1, Ral2, Ral9, Ra20, and Ra21 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, or aryl;
each Ral3 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Ral1, Ral2, Ral3, Ral9, Ra20, Ra21, and Ra35, and each cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl of Ra58 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, -
NRa22Ra23 _0Ra24 and _SF5. wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRa36Ra37, -NRa38C(0)Ra39, -ORa40, and Ra59, wherein each Ra59 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Ra59 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -ML·, -SFs, -OH,
-O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl each R322, Ra23, R324, Ra36, Ra37, Ra38, Ra39, and Ra40 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; and n is an integer from 0 to 1 1.
8. The compound of claim 6 or 7, wherein the compound is of Formula (I-A):
Figure imgf000340_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7, and B, X, Ral, Ra2, Ra3, Ra4, Ra5, and n are as defined for Formula (I).
9. The compound of claim 6 or 7, wherein the compound is of Formula (I-B):
Figure imgf000340_0002
or a pharmaceutically acceptable salt thereof, wherein:
Y is -C(Ra45)2-,— S(0)r— , -0-, or -N(Ra45)-, wherein each Ra45 is independently hydrogen or Ra4;
X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, -C(O)-, or -C(Ra6)2-, wherein when Y is -CH2- and B is phenyl, X is -S(O)-, -S(0)2-, -S(0)NRa46-, -C(S)-, or -C(Ra6)2-; r is 0, 1, or 2; p is an integer from 0 to 7;
and B, Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra46, and n are as defined for Formula (I).
10. The compound of claim 5 or 9, or a pharmaceutically acceptable salt thereof, wherein Y is -CH2-.
11. The compound of any one of claims 1, 2, 6, or 7, or a pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heteroaryl.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein B is heteroaryl, cycloalkyl, or heterocycloalkyl.
14. The compound of any one of claims 1 to 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.
15. The compound of any one of claims 1 to 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.
16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein B is (C9-Cio)bicyclic aryl.
17. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein B is (C5-Cio)cycloalkyl.
18. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein B is phenyl.
19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein at least one Ra5 is:
unsubstituted or substituted alkyl, wherein the alkyl is branched;
-NRallRa12, wherein at least one of Ral1 and Ral2 is not hydrogen; or (Ci-C2)alkyl substituted with one or more substituents independently selected from the group consisting of =0, -NR320! 321, and Ra58, wherein Ra58 is heterocycloalkyl and at least one of Ra20 and R321 is not hydrogen.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein both Ral1 and Ral2 are not hydrogen.
21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein at least one of Ral1 and Ral2 is substituted alkyl.
22. The compound of any one of claims 19 to 21, or a pharmaceutically acceptable salt thereof, wherein Ral1 is alkyl substituted with aryl, wherein the aryl is unsubstituted or substituted.
23. The compound of any one of claims 19 to 22, or a pharmaceutically acceptable salt thereof, wherein Ral2 is alkyl substituted with one or more substituents independently selected from the group consisting of =0, -NRa22Ra23, -OR324, and heterocycloalkyl, wherein the heterocycloalkyl is independently unsubstituted or substituted.
24. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein at least one R35 is Ci-alkyl substituted with -NRa20Ra21, wherein at least one of R320 and R321 is not hydrogen.
25. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein at least one R35 is C2-alkyl substituted with =0 and -NRa20Ra21, wherein at least one of R320 and Ra21 is not hydrogen.
26. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein at least one R35 is substituted alkyl, wherein the alkyl is isopropyl, wherein the isopropyl is substituted with two or more substituents independently selected from the group consisting of
=0, -NR^R321, -OR319, and R358; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R358 is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkynyl, -CN, and =0, and wherein each alkyl is independently unsubstituted or substituted with one or more halo.
27. The compound of any one of claims 19 or 24 to 26, or a pharmaceutically acceptable salt thereof, wherein Ra20 and Ra21 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 with one or more substituents independently selected from the group consisting of halo, =0, -NRa22Ra23, -ORa24, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; wherein 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, haloalkyl, and -NRa36Ra37; and wherein at least one of Ra20 and Ra21 is not hydrogen.
28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein both Ra20 and Ra21 are not hydrogen.
29. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein one or more Ra5 is -NRallRa12, wherein:
Ral1 is Ci-alkyl substituted with aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and
Ral2 is hydrogen or alkyl, wherein the alkyl is substituted with one or more substituents independently selected from the group consisting of =0, aryl, heteroaryl, -NRa22Ra2\ and -ORa24;
wherein 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.
30. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein one or more Ra5 is a substituted alkyl of formula (a):
Figure imgf000343_0001
wherein: w is 0 or 1;
Ra20 and Ra21 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
independently selected from the group consisting of halo, =0, -NRa22Ra2\ -ORa24, 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.
31. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein one or more Ra5 is alkyl, wherein the alkyl is isopropyl, wherein each terminal methyl of the isopropyl is independently substituted with one or more substituents independently selected from the group consisting of =0, -NRa20Ra2 1, -ORa19, and Ra58; wherein each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of Ra58 is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -CN, alkynyl, halo, and alkyl, and wherein each alkyl is independently unsubstituted or substituted with one or more halo.
32. The compound of claim 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.
33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt thereof, wherein one terminal methyl of the isopropyl is substituted with =0 and -NRa20Ra21 or =0 and Ra58, wherein Ra58 is heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted.
34. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein one or more Ra5 are independently selected from the group consisting of halo;
-0-(Ci-C4)alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3-C6)cycloalkyl unsubstituted or substituted with one or more fluoro or chloro; and (Ci-Ce)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3- C6)cycloalkyl, (C3-C6)heterocycloalkyl, aryl, heteroaryl, halo, -OH, -0-(Ci-C4)alkyl, =0,
— NRa20Ra21 , and -CN.
35. The compound of any one of claims 1 to 3 or 19 to 34, wherein the compound is of Formula (X-A-i):
Figure imgf000345_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X).
36. The compound of any one of claims 6 to 8 or 19 to 34, wherein the compound is of Formula (I-A-i):
Figure imgf000345_0002
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7.
37. The compound of any one of claims 1, 2, 4, or 19 to 34, wherein the compound is of Formula (X-C-i):
Figure imgf000346_0001
or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7 and X, Rxl, Rx2, Rx3, Ral, Ra2, Ra3, Ra4, and Ra5 are as defined in Formula (X).
38. The compound of any one of claims 1 to 18 or 34 to 37, or a pharmaceutically acceptable salt thereof, wherein at least one of Ra5 is:
Figure imgf000346_0002
wherein:
Ra25 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORa28, -SFs, and
-NRa29Ra30;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -SFs, =0, -ORa31,
-NRa41Ra42, -NRa43C(0)Ra44, cycloalkyl, and heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, halo,
-OH, and -SFs; each Ra26 and Ra27 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, -ORa32, and
-NRa33Ra34; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, -OH, =0, and -SFs; or one Ra26 and one R327 attached to the same atom, 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 Ra2X, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra41, Ra42, Ra43, and Ra44 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein q is 1 and Ra26 is hydrogen.
40. The compound of any one of claims 1 to 18 or 34 to 39, or a pharmaceutically acceptable salt thereof, wherein at least one Ra5 is heteroaryl or heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -SFs, and Ra35.
41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein Ra35 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein Ra2 and Ra3, together with the atom to which they are attached, form a (C3- C5)cycloalkyl or a 3- to 5-membered heterocycloalkyl.
43. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein X is -S(0)2-, and Ral and one Ra4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
44. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein Ra2 and one Ra4, together with the atoms to which they are attached, form a (C3-C6)cycloalkyl or a 3- to 6-membered heterocycloalkyl.
45. The compound of any one of claims 1 to 41, or 43, or a pharmaceutically acceptable salt thereof, wherein Ra2 and Ra3 are each hydrogen.
46. The compound of any one of claims 1 to 42, 44, or 45, or a pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
47. The compound of any one of claims 1 to 42, 44, or 45, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
48. The compound of any one of claims 1 to 42, 44, or 45, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-.
49. The compound of any one of claims 1 to 34 or 38 to 48, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
50. The compound of any one of claims 1, 2, 6, 7, 11 to 34, or 38 to 49, or a
pharmaceutically acceptable salt thereof, wherein m is 0.
51. The compound of any one of claims 3 to 5, 8 to 10, or 13 to 49, or a pharmaceutically acceptable salt thereof, wherein p is 0.
52. The compound of any one of claims 1 to 12, 19 to 34, 38 to 48, 50, or 51, or a pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
53. The compound of any one of claims 1, 2, 6, 7, 19 to 34, or 38 to 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.
54. The compound of any one of claims 1 to 5, 10 to 35, or 37 to 53, or a pharmaceutically acceptable salt thereof, wherein Rxl is hydrogen.
55. The compound of any one of claims 1 to 5, 10 to 35, 37 to 54, or a pharmaceutically acceptable salt thereof, wherein Rx2 and Rx3 are hydrogen.
56. The compound of any one of claims 1 to 5, 10 to 35, or 37 to 55, or a
pharmaceutically acceptable salt thereof, wherein one of Rxl, Rx2, and Rx3 is unsubstituted or substituted alkyl.
57. The compound of claim 1, wherein the compound is:
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
pharmaceutically acceptable salt of any of the foregoing.
58. A compound of claim 1 or 6, wherein the compound is:
Figure imgf000351_0002
Figure imgf000352_0001
Figure imgf000353_0001
eptable salt of any of the foregoing.
59. The compound of claim 1 or 6, wherein the compound is:
Figure imgf000353_0002
Figure imgf000354_0001
f the foregoing.
60. The compound of claim 1, wherein the compound is:
Figure imgf000354_0002
Figure imgf000355_0001
Figure imgf000355_0002
pharmaceutically acceptable salt of any of the foregoing.
61. A pharmaceutical composition comprising a compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
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 claims 1 to 60, or a pharmaceutically acceptable sat thereof, and a pharmaceutically acceptable excipient.
63. The method of claim 62, wherein the K-Ras protein is human K-Ras4b.
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 claims 1 to 60, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
65. The method of claim 64, wherein the disorder is cancer.
66. The method of claim 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.
67. The method of claim 64, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
68. The method of any one of claims 64 to 67, wherein the disorder is associated with a mutation of K-Ras.
69. Use of a compound of any one of claims 1 to 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.
70. The use of claim 69, wherein the K-Ras protein is human K-Ras4b.
71. Use of a compound of any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
72. The use of claim 71, wherein the disorder is cancer.
73. The use of claim 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.
74. The use of claim 71, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
75. The use of any one of claims 71 to 74, wherein the disorder is associated with a mutation of K-Ras.
76. A compound according to any one of claims 1 to 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.
77. The compound for use of claim 76, wherein the K-Ras protein is human K-Ras4b.
78. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
79. The compound for use in claim 78, wherein the disorder is cancer.
80. The compound for use of claim 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.
81. The compound for use of claim 78, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
82. The compound for use of any one of claims 78 to 81, wherein the disorder is associated with a mutation of K-Ras.
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