WO2019204449A1 - K-ras modulators with a vinyl sulfone moiety - Google Patents

K-ras modulators with a vinyl sulfone moiety Download PDF

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Publication number
WO2019204449A1
WO2019204449A1 PCT/US2019/027883 US2019027883W WO2019204449A1 WO 2019204449 A1 WO2019204449 A1 WO 2019204449A1 US 2019027883 W US2019027883 W US 2019027883W WO 2019204449 A1 WO2019204449 A1 WO 2019204449A1
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alkyl
heterocycloalkyl
formula
cycloalkyl
heteroaryl
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PCT/US2019/027883
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French (fr)
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Anna E. Maciag
David Turner
Matthew Alexander James Duncton
Vandana KUMARI
Adam R. Renslo
Eddy Low
Christopher BRASSARD
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Theras, Inc.
Leidos Biomedical Research, Inc.
The Regents Of The University Of California
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Publication of WO2019204449A1 publication Critical patent/WO2019204449A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure relates generally to compounds that inhibit K-Ras, or the post-translational processing of RAS that produces a K-Ras protein, and more specifically to inhibitors with a vinyl sulfone 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 the RAS/MAPK signaling pathway.
  • K-Ras is a GTPase that acts as a molecular switch, flipping between an active GTP-bound form and an inactive GDP -bound form.
  • the K-Ras protein plays a crucial role in tissue signaling, and is involved in cell proliferation, cell differentiation, and apoptosis.
  • 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 KRAS that produces a mature fully-processed K-Ras protein.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • W is aryl or heteroaryl
  • X is -S(O)-, -S(0)2-, -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ;
  • each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl
  • R bl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0, 1, or 2;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N0 2 ,-NR bl3 R bl4 , -OR b15 , -S0 2 R bl6 , and -S0 2 NH 2 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl, z is 1; each R b4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -N0 2 , -CN, -S0 2 NH 2 ,
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or R b8 and R bl , together with the atoms to which they are attached, form a
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or two to four R b2 , R b3 , R b6 , and R b7 , together with the atoms to which they are
  • heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo; or R bl and one R b4 , together with the atoms to which they are attached, form a
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or two to four R b4 , 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; each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -N0 2 , -CN,
  • R M8, R bW R b22 ⁇ R b23 ⁇ R b24 ⁇ R b25 ⁇ R b26 ⁇ R b27 ⁇ and R b28 ⁇ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R b65 is
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR b29 R b3 °, -SFs, and -OR b31 ;
  • each R b29 , R b30 , R b31 , R b43 , R b44 , R b45 , R b46 , and R b47 is independently
  • each R bl2 is independently selected from the group consisting of halo, alkyl,
  • haloalkyl and -OR b32 , wherein R b32 is hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • t is an integer from 0 to 6.
  • A is 5- or 6-membered heterocycloalkyl.
  • the compound of Formula (I) is a compound of Formula (II):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • W is aryl or heteroaryl
  • X is -S(O)-, -S(0)2-, -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ;
  • each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl
  • R bl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl
  • z is 0 or 1;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N0 2 ,-NR bl3 R bl4 , -OR b15 , -S0 2 R bl6 , and -S0 2 NH 2 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl, z is 1; each R b4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -N0 2 , -CN, -S0 2 NH 2 ,
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or R b8 and R bl , together with the atoms to which they are attached, form a
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or two to four R b2 , R b3 , R b6 , and R b7 , together with the atoms to which they are
  • heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo; or R bl and one R b4 , together with the atoms to which they are attached, form a
  • heterocycloalkyl unsubstituted or substituted with one or more halo; or two to four R b4 , 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; each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -N0 2 , -CN,
  • R M8, R bW R b22 ⁇ R b23 ⁇ R b24 ⁇ R b25 ⁇ R b26 ⁇ R b27 ⁇ and R b28 ⁇ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R b65 is
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NR b29 R b3 °, -SFs, and -OR b31 ;
  • each R b29 , R b30 , R b31 , R b43 , R b44 , R b45 , R b46 , and R b47 is independently
  • each R bl2 is independently selected from the group consisting of halo, alkyl,
  • haloalkyl and -OR b32 , wherein R b32 is hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • t is an integer from 0 to 6.
  • A is 5- or 6-membered
  • the compound of Formula (II) is a compound of Formula (P-A):
  • the compound of Formula (II) is a compound is of Formula (II- A-ii):
  • the compound of Formula (II) is a compound of Formula (P-B):
  • the compound of Formula (II) is a compound of Formula (II- B-ii):
  • p is an integer from 0 to 7;
  • Y is -C(R b52 )2-, -S(0)— , -0-, or -N(R b52 )-, wherein each R b52 is independently hydrogen or R b4 ;
  • r is 0, 1, or 2;
  • u is an integer from 0 to 5; and
  • B, X, R b4 , R b5 , R bl °, R bu , R bl2 , and n are as defined for Formula (II).
  • Y is -CH2-.
  • B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the
  • heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is a 9- or 10- membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is (C9-Cio)bicyclic aryl.
  • B is (C 5 -Cio)cycloalkyl.
  • the compound of Formula (II-B) is a compound of Formula
  • the compound of Formula (II-B) is a compound of Formula (II- B-i):
  • At least one R b5 is:
  • R b33 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R b36 , R b37 , R b38 , R b39 , R b40 , R b41 , R b42 , R b48 , R b49 , R b50 , and R b51 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
  • X is -S(0)2- In other variations, X is— C(O)— . In certain variations, X is -CFh- In some variations, n is 1 or 2. In other variations, m is 0 In certain variations, p is 0
  • At least one R bl2 is chloro.
  • a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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 (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, and a
  • the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer 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 (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof in the
  • the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
  • the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof for use in a method of treating a disorder in a subject in need thereof.
  • the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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. l is a heat map comparing the covalent labeling of the proteins GppNHp-K- Ras4b and GDP-K-Ras4b different proteins by selected compounds described herein.
  • FIG. 2 is a graph of uptake of compound 11-0017 by MiaPaCa-2 pancreas carcinoma cells over time.
  • FIG. 3 depicts images of MiaPaCa-2 cells pancreas carcinoma cells incubated with dimethyl sulfoxide (DMSO) or different concentrations of compound 11-0017 for 72 h.
  • DMSO dimethyl sulfoxide
  • Activity in cells is indicated by growth arrest.
  • FIG. 4 is a heat map of ICso values for selected compounds as measured in different mouse embryonic fibroblast cells (MEF).
  • FIG. 5 A depicts Western blot analysis of compound 11-0017 taken up by two cancer cell lines, HupT4 (pancreas cancer line bearing K-Ras G12V mutant) and H1792 (lung adenocarcinoma bearing G12C mutant).
  • FIG. 5B depicts images of cell proliferation in the presence of dimethyl sulfoxide (DMSO, control) or different amounts of compound 11-0017 in the H1792 lung
  • FIG. 6 depicts gel images of the Alexa Fluor 647 signal (negative from whole cells lysates that were not subjected to the click conjugation reaction) and positive for pull-down (Pd) of Flag-K-Ras4b from HEK293 expressing K-Ras4b G12V treated with 11-0144.
  • LMW low molecular weight standards.
  • a compound such as a compound of Formula (I), (II), (II- A), (II- A-i), (II-A-ii), (P-B), (II-B-i), or (II-B-ii), or a stereoisomer or 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 KRAS that produces a K-Ras protein, such as K-Ras4b.
  • this compound may block the famesylation of a of the newly synthesized K-Ras, preventing its C-terminal processing.
  • this compound or stereoisomer or pharmaceutically acceptable salt thereof may be administered to a subject in need thereof, for example in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.
  • a compound as described herein may be administered in a therapeutically effective amount to a subject in need thereof in a method of treating a disorder in a subject.
  • the disorder may be, for example, a disorder associated with a mutation of KRAS.
  • the disorder may be, for example, a disorder associated with a mutation in a K-Ras protein.
  • the compound inhibits K-Ras, or decreases the level of K-Ras, or inhibits the post-translational processing of KRAS to produce a K-Ras protein, such as K-Ras4b.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • W is aryl or heteroaryl;
  • X is -S(O)-, -S(0) 2- -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ; each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R bl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0, 1, or 2;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2, wherein when one of R b6 and R b7 is alkyl, z is 1;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NR bl3 R b14 , -OR b15 , -S02R b16 , and -SO2NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl, z is 1; each R b4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR bl3 R b14 , -OR b15 , 0, -SR b60 , and -S0 2 R bl6 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R b4 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;
  • each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R b29 , R b30 , R b31 , R b43 , R b44 , R b45 , R b46 , and R b47 is independently
  • each R bl2 is independently selected from the group consisting of -CN, -NIL ⁇ ,
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11; and t is an integer from 0 to 6.
  • the compound of Formula (I) is a compound of Formula (II):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • W is aryl or heteroaryl
  • X is -S(O)-, -S(0)2-, -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ;
  • each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl
  • R bl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0 or 1;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2, wherein when one of R b6 and R b7 is alkyl, z is 1;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, — NR bl3 R b14 , -OR b15 , -S02R b16 , and -SO2NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl, z is 1; each R b4 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 substituents independently selected from the group consisting of halo, -CN, -NH 2 , -NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SO3H, -SC H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHSO2H, -NHC(0)H, -NHC(O)- alkyl, -NHC(0)0-alkyl,-NHC(0)0H, -NHOH, -OH,
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R b4 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;
  • each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R b65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R bl7 R bl8 R bl9 R b20 R b21 R b22 R b23 R b24 R b25 R b26 R b27 R b54 R b55 Rb56, R bS7 R bs ⁇ R bs ⁇ R b6i ⁇ R b6 2 ⁇ R b63 ⁇ and R b64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
  • heterocycloalkyl aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R bl7 , R bl8 , R bl9 , R b22 , R b23 , R b24 , R b25 , R b26 , R b27 , and R b28 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R b65 is
  • each R bl2 is independently selected from the group consisting of -CN, -NH2,
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • t is an integer from 0 to 6.
  • 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.
  • each R bl2 is independently selected from the group consisting of-CN, -NH2, -NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SO3H, -S0 4 H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 .
  • heterocycloalkyl 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl
  • aryl such as (C6-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
  • W is aryl or heteroaryl
  • X is -S(O)-, -S(0)2-, -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ; each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl;
  • R bl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0 or 1;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NR bl3 R b14 , -OR b15 , -S02R b16 , and -SO2NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl, z is 1; each R b4 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NCte, -CN, -SO2NH2, -NR bl3 R b14 , -OR b15 , 0, -SR b60 , and -S02R b16 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R b4 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;
  • each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NCte, -CN,
  • each R b28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl is independently unsubstituted or substituted with one or more
  • each R b65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R bl7 R bl8 R bl9 R b20 R b21 R b22 R b23 R b24 R b25 R b26 R b27 R b54 R b55 R bS6 , RbS7 Rb s ⁇ Rb s ⁇ Rb6i ⁇ Rb62 ⁇ Rb63 ⁇ and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
  • heterocycloalkyl aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R bl7 , R bl8 , R bl9 , R b22 , R b23 , R b24 , R b25 , R b26 , R b27 , and R b28 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R b65 is
  • each R b66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl
  • each R bl2 is independently selected from the group consisting of halo, alkyl, haloalkyl, and -OR b32 , wherein R b32 is hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • t is an integer from 0 to 6.
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • W is aryl or heteroaryl
  • X is -S(O)-, -S(0)2-, -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ;
  • each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl
  • R bl is hydrogen, alkyl, or cycloalkyl
  • z is 0 or 1;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -CN, -OH, -NO2, -NH2, and -SO2NH2, wherein when one of R b6 and R b7 is alkyl, z is 1;
  • each R b4 is independently selected from the group consisting of halo, alkyl,
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NR bl3 R b14 , -OR b15 , 0, -SR b60 , and -S0 2 R bl6 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; and each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl,
  • haloalkyl cycloalkyl, or halocycloalkyl
  • each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NCte, -CN,
  • each R b65 is independently cycloalkyl, heterocycloalkyl, a irryyli, o orr h neetreerrooaarryyli;, each R b20 , R b21 , R b22 , R b23 ub24 T>b54 ub55 ub56 ub57 u b58 ub59 ub61 u b62 rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv , rv
  • R b63 , and R b64 is indepoendentlyv hyydroggen, alkyyl, haloalkyyl,. cyvcloalkyv l, or halocycloalkyl; each R bl7 , R bl8 , R b25 , R b26 , and R b27 is independently hydrogen, alkyl,
  • each R bl9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R bl7 , R 8 , R bl9 , R b25 , R b26 , R b27 , and R b28 , and each cycloalkyl,
  • heterocycloalkyl, aryl, and heteroaryl of R b65 is independently unsubstituted or substituted with one or more substituents
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • each R bl2 is independently selected from the group consisting of halo, alkyl, haloalkyl, and -OR b32 , wherein R b32 is hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • t is an integer from 0 to 6.
  • 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.
  • R bl is hydrogen, alkyl, halolkyl, cycloalkyl, or halocycloalkyl.
  • R bl is hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocydoalkyl.
  • R bl is hydrogen, (Ci-Ce)alkyl, or (C3-C6)cydoalkyl.
  • R bl is hydrogen.
  • R bl is (Ci-C6)alkyl.
  • R bl is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R bl is (C3-C6)cydoalkyl.
  • R bl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NCte, -NR bl3 R b14 , -OR b15 , -S02R b16 , and -SO2NH2; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl, z is 1.
  • R b6 and R b7 when one of R b6 and R b7 is alkyl or haloalkyl, z is 1. In certain embodiments, when one or both of R b6 and R b7 are independently alkyl or haloalkyl, z is 1.
  • each R bl3 , R bl4 , R bl5 , and R bl6 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl.
  • each R bl3 , R bl4 , R bl5 , and R bl6 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl.
  • each R bl3 , R bl4 , R bl5 , and R bl6 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C 3 - C6)halocycloalkyl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered
  • each R bl3 , R bl4 , R bl5 , and R bl6 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)halocydoalkyl.
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NCte,
  • R b2 , R b3 , R b6 , R b7 are independently selected from the group consisting of hydrogen, halo, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2, wherein when one of R b6 and R b7 is alkyl, z is 1
  • R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, chloro, fluoro, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and - OH, wherein when one of R b6 and R b7 is alkyl, z is 1.
  • R b6 , R b7 , R b8 , and R b9 are each hydrogen; and R bl ° and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NO2, - CN, -OH, -NH2, and -SO2NH2.
  • R b6 , R b , R b8 , and R b9 are each hydrogen; and R bl ° and R bu are independently selected from the group consisting of hydrogen, halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2.
  • one of R bl ° and R bu is hydrogen.
  • R bl ° and R bu are both hydrogen.
  • both R b6 and R b7 are alkyl, and z is 0 or 1.
  • R b6 and R b7 are independently alkyl or haloalkyl, and z is 0 or 1.
  • R b6 and R bl together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R b6 and R bl 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.
  • the heterocycloalkyl is unsubstituted.
  • R bl ° and R bl together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R bl ° and R bl together with the atoms to which they are attached, form a 3- to lO-membered
  • heterocycloalkyl or a 3- to 8-membered heterocycloalkyl, or a 3- to 6-membered
  • heterocycloalkyl or a 4- 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.
  • R b8 and R bl together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo.
  • R b8 and R bl together with the atoms to which they are attached, form a 3- to lO-membered
  • heterocycloalkyl or a 3- to 8-membered heterocycloalkyl, or a 3- to 6-membered
  • heterocycloalkyl or a 4- 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 of R b2 , R b3 , R b6 , and R b7 together with the atoms to which they are attached, form a 3- to lO-membered heterocycloalkyl, or a 3- to 8-membered heterocycloalkyl, or a 3- to 6-membered heterocycloalkyl, or a 4- 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, two to four of R b2 , R b3 , R b6 , and R b7 , together with the atoms to which they are attached, form a 5- to lO-membered heteroaryl, or a 5- to 8-membered heteroaryl, or a 5- to 6-membered heteroaryl, wherein the heteroaryl is unsubstituted or substituted with one or more halo. In some embodiments, the heteroaryl is unsubstituted.
  • R b2 , R b3 , R b6 , and R b7 together with the atoms to which they are attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo
  • the remaining one or two of R b2 , R b3 , R b6 , and R b7 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, -NR bl3 R b14 , -OR b15 , -S02R b16 , and -SO2NH2; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl
  • 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,
  • 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.
  • 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.
  • Alkynoxy refers to a -O-alkynyl moiety, wherein alkynyl is as described above.
  • 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 ((C3-C2o)cycloalkyl), 3 to 12 carbon atoms ((C3- Ci2)cycloalkyl), 3 to 8 carbon atoms ((C 3 -C8)cycloalkyl), 3 to 6 carbon atoms ((C3- C 6 )cycloalkyl), or 3 to 5 carbon atoms ((C 3 -C 5 )cydoalkyl).
  • 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).
  • the aryl may connect to one or more substituents or moieties of the formulae described herein through any atom of the fused ring for which valency permits.
  • 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).
  • heteroaryl includes groups with an aromatic ring that comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S, (e.g, pyridinyl, pyrazinyl, furanyl, thiophenyl).
  • heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom, fused to a non-aromatic hydrocarbon ring (e.g, 5,6,7,8-tetrahydroquinolinyl; 4,5,6,7-tetrahydroisobenzofuranyl).
  • heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom fused to an aromatic hydrocarbon ring (e.g, quinolinyl, quinoxalinyl, benzothiazolyl).
  • aromatic hydrocarbon ring e.g, quinolinyl, quinoxalinyl, benzothiazolyl
  • heteroaryl includes polycyclic groups with two fused aromatic rings, wherein each ring comprises at least one ring heteroatom (e.g, naphthyridinyl).
  • Heteroaryl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each ring heteroatom is independently selected from the group consisting of N, O, and S.
  • a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl.
  • Heterocycloalkyl refers to non-aromatic, monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S.
  • the heterocycloalkyl group may be saturated or unsaturated, and may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g, be a 3-membered, 4- membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10- membered, l l-membered, or l2-membered heterocycloalkyl).
  • Heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • a heterocycloalkyl has 2 to 8 ring carbon atoms and 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • heterocycloalkyl examples include, but are not limited to, oxetanyl, azetidinyl,
  • tetrahydrofuranyl tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, and tropanyl.
  • Haloheterocycloalkyl refers to a heterocycloalkyl group substituted with one or more halo, which may be selected independently.
  • haloeheterocycloalkyl includes heterocycloalkyl substituted with one or more halo independently selected from the group consisting of fluoro, chloro, iodo, and bromo.
  • Halo or“halogen” includes bromo, chloro, fluoro, and iodo.
  • substituted means a group wherein at least one hydrogen atom or electron pair is replaced by a bond to a non-hydrogen atom.
  • This may include, for example, a halogen atom such as F, Cl, Br, or I; an oxygen atom in a hydroxyl group; a nitrogen atom in an amino group; or an oxygen atom in a sulfur dioxide group.
  • “(Ci-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, C 3 , C 4 , Cs, Ce, Ci-6, Ci-s, CM, C 1-3, 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.
  • the compound of Formula (II) is a compound of Formula (II-
  • p is an integer from 0 to 7;
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7.
  • the compound of Formula (II) is a compound of Formula (II- B):
  • p is an integer from 0 to 7;
  • Y is -C(R b52 )2-,— S(0)r— , -0-, or -N(R b52 )-, wherein each R b52 is independently hydrogen or R b4 ; r is 0, 1, or 2; and
  • 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.
  • W is aryl or heteroaryl. In some embodiments, W is (C 6 -Cio)aryl. In certain embodiments, W is 5- to 8-membered heteroaryl. In certain embodiments, W is 5- to 7-membered heteroaryl. In some embodiments, W is 5-, 6-, or 7-membered heteroaryl.
  • W is 5- to lO-membered heteroaryl, wherein the heteroaryl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • W is 5- or 6-membered heteroaryl, wherein the heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • W is 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • W is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl.
  • W 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.
  • W is pyridazinyl, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, pur
  • W is:
  • W is aryl.
  • W is (C 6 -Cio)aryl, such as C 6 -aryl, (C7- Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl.
  • W is phenyl or naphthyl.
  • W 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.
  • aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring
  • W is:
  • W may be unsubstituted or substituted with one to six R bl2 as described in Formula (I), Formula (II), Formula (P-A), and Formula (P-B), as valency allows.
  • R bl2 as described in Formula (I), Formula (II), Formula (P-A), and Formula (P-B), as valency allows.
  • t is an integer from 0 to 5.
  • t is an integer from 0 to 6. In some embodiments, t is an integer from 0 to 5. In other embodiments, t is an integer from 0 to 4. In still further embodiments, t is an integer from 0 to 3. In certain embodiments, t is 0, 1, or 2. In other embodiments, t is an integer from 1 to 6, or from 2 to 6, or from 3 to 6, or from 3 to 5, or from 2 to 4. In certain embodiments, t is 0. In other embodiments, t is 1. In some embodiments, t is 2. In still other embodiments, t is 3. In still further embodiments, t is 4. In some embodiments, t is 5. In certain embodiments, t is 6.
  • W is phenyl
  • t is an integer from 0 to 5.
  • W is phenyl
  • t is an integer from 0 to 5.
  • u is an integer from 0 to 5.
  • the compound of Formula (II) is a compound of Formula (II- A-ii): -ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
  • the compound of Formula (II) is a compound of Formula (II- B-ii):
  • p is an integer from 0 to 7;
  • Y is -C(R b52 )2-,— S(0)r— , -O-, or -N(R b52 )-, wherein each R b52 is independently hydrogen or R b4 ; r is 0, 1, or 2;
  • u is an integer from 0 to 5;
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
  • Y is -C(R b52 )2-, wherein each R b52 is independently hydrogen or R b4 .
  • Y is -CFh-
  • Y is -CHR b4 -.
  • Y is -C(R b4 )2-
  • Y is— S(0)r— , where r is 0, 1, or 2.
  • Y is -S-.
  • Y is -S(O)-.
  • Y is -S(0)2- In some
  • Y is -0-. In other embodiments, Y is -N(R b52 )-, wherein R b52 is hydrogen or R b4 . For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NR b4 -.
  • B is heteroaryl, cycloalkyl, or heterocycloalkyl.
  • B is 5- to lO-membered heteroaryl, or 5- to lO-membered
  • heterocycloalkyl wherein the heteroaryl or heterocycloalkyl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is 9- or 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.
  • 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 10- membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is a 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • B is a 5,5-ring fused heteroaryl, 6,6- ring fused heteroaryl, or 5,6-ring fused heteroaryl.
  • B is pyridazinyl, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indo
  • B is:
  • B is aryl.
  • B is (C6-Cio)aryl, such as C6-aryl, (C7-Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl.
  • B is phenyl or napthyl.
  • B is an aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring, for example (C7- Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring.
  • B is:
  • B is cycloalkyl
  • B is (C3-Cio)cycloalkyl. In certain embodiments, B is (C5-Cio)cycloalkyl. In other embodiments, B is (C 5 -C7)cycloalkyl. In still other embodiments, B is (Cs- Cio)cycloalkyl. In some embodiments, B is C3-cycloalkyl, C 4 -cycloalkyl, Cs-cycloalkyl, C6- cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or C 10-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 b5 as described in Formula (I), Formula (II), Formula (P-A), Formula (II-A-ii), Formula (P-B), and Formula (II-B-ii), as valency allows.
  • B is , , , wherein n is an integer from
  • B is as described above, and * s , wherein n is an integer from 0 to 11.
  • n is an integer from 0 to 11. In some embodiments, n is an integer from 0 to 9. In other embodiments, n is an integer from 0 to 7. In still further embodiments, n is an integer from 0 to 5. In certain embodiments, n is an integer from 0 to 3. In other embodiments, n is an integer from 3 to 11, or from 5 to 11, or from 7 to 11, or from 3 to 7, or from 3 to 5. In certain embodiments, n is 0. In other embodiments, n is 1. In some embodiments, n is 2. In still other embodiments, n is 3. In still further embodiments, n is 4.
  • B is phenyl, and n is an integer from 0 to 5.
  • n is an integer from 0 to 5.
  • R b5 When multiple instances of a substituent (for example, R b5 ) are present, it should be understood that they may be optionally different unless otherwise indicated.
  • the compound of Formula (II) is a compound of Formula (II-
  • p is an integer from 0 to 7;
  • u is an integer from 0 to 5;
  • R b4 , R b5 , R bl °, R bu , and R bl2 are as defined for Formula (II).
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
  • the compound of Formula (II) is a compound of Formula (II- B-i):
  • p is an integer from 0 to 7;
  • Y is -C(R b52 )2-,— S(0)r— , -0-, or -N(R b52 )-, wherein each R b52 is independently hydrogen or R b4 ;
  • r 0, 1, or 2;
  • u is an integer from 0 to 5;
  • R b4 , R b5 , R bl °, R bu , and R bl2 are as defined for Formula (II).
  • Y is -C(R b52 )2-, wherein each R b52 is independently hydrogen or R b4 . In certain embodiments, Y is -CFh- In other
  • Y is -CHR b4 -. In some embodiments, Y is -C(R b4 )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
  • Y is -O-. In other embodiments, Y is -N(R b52 )-, wherein R b52 is hydrogen or R b4 . For example, in certain embodiments, Y is -NH-. In other embodiments, Y is -NR b4 -.
  • p is an integer from 0 to 6, or an integer from 0 to 5, or an integer from 0 to 4, or an integer from 0 to 3, or an integer from 0 to 2, or an integer from 3 to 5. In some embodiments, p is 0. In other embodiments, p is 1. In still further embodiments, p is 2. In some embodiments, p is 3. In other embodiments, p is an integer from 4 to 7. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
  • R bl2 (for example, R bl2 ) are present, it should be understood that they may be optionally different unless otherwise indicated.
  • each R bl2 is independently selected from the group consisting of halo, alkyl, haloalkyl, and -OR b32 , wherein R b32 is hydrogen, alkyl, or haloalkyl.
  • each R bl2 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, -OH, -0-(Ci-C 6 )alkyl, and -0-(Ci-C 6 )haloalkyl.
  • each R bl2 is independently fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2,
  • each R bl2 is independently fluoro, chloro, -OCH 3 , or -CF 3.
  • each R bl2 is independently fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH 3 , -OCH2CH 3 , -OCH(CH3)2, -CH2F, -CHF2, -CF 3 , -OCH2F, -OCHF2, or -OCF 3.
  • each R bl2 is independently fluoro, chloro, -OCH 3 , or -CF3.
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl.
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl.
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C 3 - C6)halocycloalkyl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered haloheterocycloalkyl.
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, (C3-C6)cycloalkyl, and (C 3 - C 6 )halocycloalkyl.
  • each R b4 is independently selected from the group consisting of fluoro, chloro, bromo, (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )halocycloalkyl, 3 to 6-membered heterocycloalkyl, -NO2, -CN, -SO2NH2, -NH2, -NH(Ci-C 6 )alkyl, -N((Ci-C 6 )alkyl)((Ci-C 6 )alkyl), -OH, -0-(Ci
  • each R b4 is independently selected from the group consisting of fluoro, chloro, bromo, (Ci-Ce)alkyl, (Ci- C 6 )haloalkyl, -OH, -0-(Ci-C 6 )alkyl, and -0-(Ci-C 6 )haloalkyl.
  • At least one R b4 is fluoro, chloro, bromo, (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, -OH, -0-(Ci-C 6 )alkyl, or -0-(Ci- C 6 )haloalkyl.
  • at least one R b4 is fluoro, chloro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2, or -CF3.
  • heterocycloalkyl wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is
  • two to four R b4 together with the atoms to which they are attached, form a (C 6 -Cio)aryl, 3 to 6-membered heteroaryl, (C 3 -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 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted.
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is fused with ring A.
  • the cycloalkyl or heterocycloalkyl forms a spirocyclic system with ring A.
  • two to four R b4 together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or
  • heterocycloalkyl wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is
  • one or more R b5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, -0-(Ci-C 6 )alkyl, and -0-(Ci-C 6 )haloalkyl.
  • each R b5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, -0-(Ci-C 6 )alkyl, and -0-(Ci-C 6 )haloalkyl.
  • each R b5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, -0-(Ci-C 6 )alkyl, and -0-(Ci-C 6 )haloalkyl.
  • Rb 5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci- C 6 )haloalkyl, -0-(Ci-C 6 )alkyl, -0-(Ci-C 6 )haloalkyl, and -CN.
  • one or more R b5 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci- C 6 )haloalkyl, -0-(Ci-C 6 )alkyl, -0-(Ci-C 6 )haloalkyl, and -CN.
  • one or more R b5 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F,
  • phenyl 0, -SO2NH2, -CN, cyclopropyl, cyclohexyl, and -OCH2CCH.
  • At least one R b5 is alkyl, wherein each alkyl is independently unsubstituted or substituted with one or more
  • each R b65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each
  • R b65 is independently (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • at least one R b5 is alkyl, wherein the alkyl is independently unsubstituted or substituted with one or more substituents
  • cycloalkyl 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 other embodiments, the alkyl is (Ci-C8)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In further embodiments, the alkyl is (Ci- C6)alkyl, wherein the alkyl is unsubstituted or substituted as described above.
  • the alkyl is (Ci-C 4 )alkyl, wherein the alkyl is unsubstituted or substituted as described above.
  • at least one R b5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, difluoromethyl, or fluoromethyl.
  • At least one R b5 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more
  • each R b28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R b28 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R b28 is unsubstituted alkyl.
  • R b28 is unsubstituted (Ci-C6)alkyl.
  • R b28 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
  • each R b28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • at least one R b5 is unsubstituted cycloalkyl.
  • each R b28 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6- Cio)aryl, or 3- to 8-membered heteroaryl.
  • R b28 is unsubstituted (Ci-C6)alkyl.
  • heterocycloalkyl -NR b29 R b3 °, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl.
  • at least one R b5 is unsubstituted aryl.
  • each R b28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R b28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R b28 is independently alkyl, cycloalkyl, heterocycloal
  • heterocycloalkyl (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R b28 is unsubstituted (Ci-C6)alkyl.
  • at least one R b5 is unsubstituted heteroaryl.
  • each R b28 is independently (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl.
  • R b28 is unsubstituted (Ci-C6)alkyl.
  • at least one R b5 is
  • each R bl7 , R bl8 , R bl9 , R b20 is independently selected from a stereoisomer or pharmaceutically acceptable salt thereof.
  • R b64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
  • each R b!7 is independently selected from the group consisting of: aryl, heteroaryl, alkynyl, or haloalkynyl.
  • each R b!7 is independently selected from the group consisting of: aryl, heteroaryl, alkynyl, or haloalkynyl.
  • R b62 , R b63 , and R b64 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.
  • each R b20 , R b21 , R b22 , R b23 , R b24 , R b54 , R b55 , R b56 , R b57 , R b58 , R b59 , R b61 , R b62 , R b63 , and R b64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl.
  • each R b20 , R b21 , R b22 , R b23 , R b24 , R b25 , R b54 , R b55 , R b56 , R b57 , R b58 , R b59 , R b61 , R b62 , R b63 , and R b64 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocycloalkyl.
  • each R bl7 , R bl8 , R b25 , R b26 , and R b27 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, each R bl7 , R bl8 ,
  • R b25 , R b26 , and R b27 is independently hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 10- membered heterocycloalkyl, 3- to lO-membered heteroaryl, or (C6-Cio)aryl.
  • each R bl9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl.
  • each R bl9 is independently hydrogen, (Ci- C6)alkyl, (C3-C6)cycloalkyl, 3- to lO-membered heterocycloalkyl, (C6-Cio)aryl, 3- to 10- membered heteroaryl, or (C3-C6)alkynyl.
  • one or more R b5 are independently selected from the group consisting of halo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro; -0-(C2-C 4 )alkynyl; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3-C6)cycloalkyl unsubstituted or substituted with one or more fluoro; and (Ci-Ce)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C6)cycl
  • one or more R b5 are independently selected from the group consisting of chloro; fluoro; bromo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro; -0-(C2-C 4 )alkynyl; and -CN.
  • n is 1 or 2
  • each R b5 is independently selected from the group consisting of chloro; fluoro; bromo; -0-(Ci- C6)alkyl unsubstituted or substituted with one or more fluoro; -0-(C2-C 4 )alkynyl; and -CN.
  • each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R bl7 , R bl8 , R bl9 , R b22 , R b23 , R b24 , R b25 , R b26 , R b27 , and R b28 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R b65 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, 0, -CN, aryl, heteroaryl, al
  • heterocycloalkyl -NR b29 R b3 °, -SFs, and -OR b31 , wherein each aryl, heteroaryl, alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents
  • each R b29 , R b30 , R b31 , R b43 , R b44 , R b45 , R b46 , and R b47 is independently hydrogen, alkyl, or haloalkyl.
  • each R b29 , R b30 , R b31 , R b43 , R b44 , R b45 , R b46 , and R b47 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl.
  • At least one R b5 is:
  • R b33 is hydrogen, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is
  • each R b34 and R b35 are independently hydrogen, halo, or alkyl
  • each R b36 , R b37 , R b38 , R b39 , R b40 , R b41 , R b42 , R b48 , R b49 , R b50 , and R b51 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl.
  • each R b36 , R b37 , R b38 , R b39 , R b40 , R b41 , R b42 , R b48 , R b49 , R b50 , and R b51 is independently hydrogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, or halobutyl.
  • substituents independently selected from the group consisting of halo, -SFs, (C3-
  • R b33 is (Ci-Ce)alkyl, wherein the alkyl is unsubstituted or substituted with one or more (C6-Cio)aryl or 3- to 6-membered heteroaryl.
  • R b33 is unsubstituted (Ci-C6)alkyl. In other embodiments, R b33 is (Ci-Ce)alkyl substituted with 3- to 6-membered heteroaryl. In other embodiments, R b33 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 b33 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 b33 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 b33 is (C3-C 6 )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-C 6 )alkyl.
  • R b33 is 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C 6 )alkyl.
  • R b33 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 b33 is heteroaryl, wherein the heteroaryl is
  • R b33 is alkynyl. In certain embodiments, R b33 is (C2- C 6 )alkynyl. [0135] In certain embodiments, R b33 is:
  • R b33 is:
  • R b34 and R b35 attached to the same carbon form a cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • the cycloalkyl is a (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
  • R b34 and R b35 attached to the same carbon form an unsubstituted cyclopropyl or cyclobutyl.
  • R b34 and R b35 attached to the same carbon form a cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl are substituted with one or more halo.
  • each R b34 and R b35 is hydrogen.
  • At least one R b34 or R b35 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, aryl, 3- to 6-membered heteroaryl, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -ML ⁇ , -NH(Ci-C6)alkyl, -N((Ci- C6)alkyl)((Ci-C6)alkyl).
  • one R b34 or one R b35 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 b34 or one R b35 is (Ci-Ce)alkyl, wherein the alkyl is unsubstituted or substituted with fluoro, chloro, (C3-C6)cycloalkyl, (C3)halocycloalkyl, or -OH.
  • one R b34 or one R b35 is ethyl substituted with
  • the 4- to lO-membered heterocycloalkyl is a polycyclic heterocycloalkyl.
  • at least one R b34 or R b35 is alkyl substituted with 5- to 6-membered heteroaryl.
  • q is 1. In still other embodiments, q is 2. In some
  • q is 1, and one of R b34 or R b35 is hydrogen. In other embodiments, q is 2, and one R b34 and two R b35 are hydrogen. In other embodiments, q is 2, and two R b34 and one R b35 are hydrogen. In some embodiments, q is 2, and two R b34 and three R b35 are hydrogen. In some embodiments, q is 2, and three R b34 and two R b35 are hydrogen. [0141] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
  • X is -S(O)-, -S(0) 2- ,
  • X is -S(0) 2- , -C(O)-, or -C(R bl3 ) 2- .
  • X is -S(0) 2- , -C(O)-, or -C(R bl3 ) 2-
  • X is -S(O)-, -S(0) 2- , or -S(0)NR b53 -.
  • X is -C(S)-, -C(O)-, or -C(R bl3 ) 2-
  • X is -S(O)-.
  • X is -S(0) 2-
  • X is -S(0)NR b53 -, wherein
  • R b53 is hydrogen.
  • R b53 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 bl3 )2-, wherein each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl. In certain embodiments, each R bl3 is independently hydrogen, halo, (Ci-Ce)alkyl, or (Ci-C 6 )haloalkyl.
  • each R bl3 is independently hydrogen, chloro, fluoro, methyl, ethyl, propyl, -CFhF, -CHF2, or -CF3. In some embodiments, each R bl3 is H, and X is -CH2-.
  • X is -S(0)2-, -C(O)-, or -CH2-.
  • the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii) is:
  • the compound of Formula (I) or Formula (II) is:
  • the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii) is:
  • the compound of Formula (I) or Formula (II) is:
  • the compounds described herein including compounds of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or their stereoisomers or pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, or other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( R )- or ( 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-pressure liquid chromatography (HPLC).
  • R bl ° and R bu in a cis orientation are also provided herein.
  • the compounds described herein contain other 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.
  • “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, dodecyl sulfuric acid, ethane- l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,
  • Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, pur
  • the compounds provided herein including compounds of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II- B), Formula (II-B-i), or Formula (II-B-ii), or their stereoisomers or pharmaceutically acceptable salts, also include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds may have the present structures except for the replacement of a hydrogen by a deuterium (D or 2 H) or tritium (3 ⁇ 4), or the
  • the compounds disclosed herein such as a compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, may be prepared, for example, through the reaction routes depicted in General Scheme II- 1, General Scheme II-2, and General Scheme II-3.
  • General Scheme II- 1 provides two routes to prepare a compound disclosed herein, such as a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or pharmaceutically acceptable salt thereof.
  • compound 11-102 is combined with /er/-butyl but-3- yn-l-yl carbamate (compound 11-104), RhCl(PPh3)3, and solvent (such as dichloroethane, DCE), and that mixture stirred at room temperature to produce compound 11-106.
  • This compound is then combined with meta-chloroperoxybenzoic acid (wCPBA) and solvent (such as dichloromethane, DCM), and that mixture stirred from 0 °C to room temperature to produce compound 11-108.
  • wCPBA meta-chloroperoxybenzoic acid
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • DCM solvent
  • Compound 11-110 is combined with compound 11-112, l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate (HATU), triethylamine (Et 3 N), and solvent (such as DCM), and stirred at room temperature to produce compound 11-114.
  • HATU oxid hexafluorophosphate
  • Et 3 N triethylamine
  • solvent such as DCM
  • the product 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.
  • solvent such as DCM
  • R B a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
  • This mixture is then stirred at room temperature to produce compound 11-118, an example of a compound of Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • the product in route (B) may be combined with triethylamine, solvent (such as DCM), HATU, and an R B - COOH reactant, and stirred at room temperature to produce compound 11-118, an example of a compound of Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • General Scheme II-2 provides another route to prepare a compound disclosed herein, such as a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A- ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or
  • compound 11-202 is combined with 4-(trifluoromethyl)thiophenol (compound 11-204), Pd(OAc)2, and solvent (such as tetrahydrofuran, THF), and stirred at room temperature to produce compound 11-206.
  • solvent such as tetrahydrofuran, THF
  • compound 11-208 which is an example of a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • solvent such as DCM
  • General Scheme II-3 provides two routes to prepare a compound disclosed herein, such as a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or pharmaceutically acceptable salt thereof.
  • compound 11-302 is combined with /er/-butyl but-3- yn-l-yl carbamate (compound 11-304), Cp2Zr(H)Cl, and solvent (such as tetrahydrofuran, THF), and that mixture stirred from room temperature to 60 °C to produce compound 11-306.
  • This compound is then combined with TFA and solvent (such as DCM) and stirred from 0 °C to room temperature to produce compound 11-308.
  • Compound 11-308 is combined with compound 11-310, HATU, triethylamine, and solvent (such as DCM), and stirred at room temperature to produce compound 11-312.
  • This compound is combined with TFA and a solvent (such as DCM) and stirred from 0 °C to room temperature to remove the BOC protecting group and produce compound 11-314.
  • compound 11-314 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.
  • solvent such as DCM
  • R B an R B - carbonyl chloride reactant
  • the R B is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
  • This mixture is then stirred at room temperature to produce compound 11-316, an example of a compound of Formula (II), Formula (P-A), Formula (II- A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • compound 11-314 may be combined with triethylamine, solvent (such as DCM), HATU, and an R B -COOH reactant, and stirred at room temperature to produce compound 11-316, an example of a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • compounds wherein ring A is other than 5- or 6-membered heterocycloalkyl; wherein ring A is substituted; ring W is other than phenyl, or comprises substituents other than Cl; wherein R b6 , R b7 , R b8 , R b9 , R bl °, or R bu are other than hydrogen; or z is other than 1, may also be synthesized using routes analogous to General Schemes II- 1, II-2, and II-3.
  • one or more other solvents are used in one or more steps.
  • an amine other than triethylamine is used in one or more steps.
  • the temperature may be adjusted.
  • composition comprising a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient may include, for example, an adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans.
  • Pharmaceutically acceptable excipients may include, but are not limited to, water, NaCl, normal saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors.
  • kits for treating a disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II- B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • methods of treating a disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a
  • composition comprising a compound of Formula (I), Formula (II), Formula (II-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II- B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • 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 (I), Formula (II),
  • the disorder is related to K-Ras, for example a disorder associated with a mutation of K-Ras or
  • the disorder is related to the KRAS gene, for example a disorder associated with a mutation of the KRAS gene or dysregulation of the KRAS gene. Mutation or dysregulation of K-Ras or KRAS may include mutation or dysregulation of human K-Ras4a and/or human K-Ras4b. In some embodiments, the disorder is related to the K-Ras (for example, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, for example a disorder related to aberrant K-Ras signaling pathway activity. In some embodiments, the disorder is related mutation or dysregulation of human K-Ras4b. In certain embodiments, the disorder is related to aberrant K-Ras4b signaling pathway activity.
  • K-Ras4as for example, human K-Ras4a and/or human K-Ras4b
  • the disorder is related mutation or dysregulation of human K-Ras4b. In certain embodiments, the disorder is related to aberrant
  • 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 camcer is related to the KRAS gene, for example a cancer associated with a mutation of the KRAS gene or dysregulation of the KRAS gene. Mutation or dysregulation of K-Ras or KRAS may include mutation or dysregulation of human K-Ras4a and/or human K-Ras4b.
  • the cancer is related to the K-Ras (for example, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, for example cancer related to aberrant K-Ras signaling pathway activity.
  • the cancer is related to a mutation or dysregulation of human K-Ras4b.
  • the cancer is related to aberrant K-Ras4b signaling pathway activity.
  • the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
  • the cancer is breast cancer. In other embodiments, the cancer is pancreatic cancer. In still further embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is lung cancer. In some embodiments, the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, is co-administered with one or more chemotherapeutic agents to a subject in need thereof.
  • a method of reducing the level of a K-Ras protein in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A- i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the K-Ras protein is human K-Ras4a and/or human K-Ras4b.
  • the K-Ras is human K-Ras4b.
  • the K-Ras is human K-Ras4a. In some embodiments, the K-Ras is aberrant K-Ras. In some embodiments, the K-Ras is mutant K-Ras. Reduction of the level of K-Ras may be evaluated, for example, by an 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 (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, to a subject may block one or more post-translational processing steps of a K-Ras precursor (such as K- Ras4a precursor or K-Ras4b precursor). This unprocessed precursor may then be degraded by the body, thus reducing the level of K-Ras protein.
  • K-Ras precursor such as K- Ras4a precursor or K-Ras4b precursor
  • the compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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.
  • a K-Ras precursor such as K-Ras4a precursor or K-Ras4b precursor
  • the post-translational modification that is blocked is famesylation.
  • 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 (I), Formula (II), Formula (P-A), Formula (II-A- i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the K-Ras protein is human K-Ras4a and/or human K-Ras4b.
  • the K-Ras is human K- Ras4b.
  • both the activity of K-Ras and the level of K-Ras are reduced in a subject in need thereof.
  • Effective amount or“therapeutically effective amount” refer to that amount of a compound of the disclosure that, when administered to a mammal, for example a human, is sufficient to effect treatment.
  • the amount of a compound of the disclosure which constitutes a“therapeutically effective amount” may vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated.
  • the terms“treat,” “treating,” or “treatment” refer to any indicia of success in the amelioration of an injury, disease, disorder, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, disorder, pathology, or condition more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of injury, disease, disorder, pathology, or condition; making the final point of degeneration less debilitating; improving a subject’s physical or mental well-being; or relieving or causing regression of the injury, disease, disorder, pathology, or condition.
  • the treatment of symptoms can be based on objective or subjective parameters, which may include the results of a physical examination, a neuropsychiatric exam, and/or a psychiatric evaluation.
  • Certain methods disclosed herein may treat cancer by, for example, decreasing the incidence of cancer, causing remission of cancer, slowing the rate of growth of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis, reducing the growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combinations thereof.
  • Co-administer includes administering a compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or composition comprising any of these as described herein at the same time, just prior to, or just after the administration of one or more additional therapies, such as a chemotherapeutic agent.
  • additional therapies such as a chemotherapeutic agent.
  • One or more compounds or salts thereof disclosed herein and one or more additional therapies may be co-administered as a single combination form, or may be co-administered as two or more separate forms simultaneously or sequentially.
  • Embodiment 1-1 A compound of Formula (I):
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • W is aryl or heteroaryl
  • X is -S(O)-, -S(0)2-, -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ;
  • each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl
  • R bl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl
  • z 0, 1, or 2;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N0 2 ,-NR bl3 R bl4 , -OR b15 , -S0 2 R bl6 , and -S0 2 NH 2 , wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of R b6 and R b7 is alkyl, z is 1; each R b4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO2, -CN, -SO
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo;
  • heterocycloalkyl unsubstituted or substituted with one or more halo
  • R b4 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;
  • each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R b28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each alkyl is independently unsubstituted or substituted with one or more
  • each R b65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R bl7 R bl8 R bl9 R b20 R b21 R b22 R b23 R b24 R b25 R b26 R b27 R b54 R b55 Rb56, R bS7 R bs ⁇ R bs ⁇ R b6i ⁇ R b62 ⁇ R b63 ⁇ and R b64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of R bl7 , R bl8 , R bl9 , R b22 , R b23 , R b24 , R b25 , R b26 , R b27 , and R b28 , and each
  • each R b29 , R b30 , R b31 , R b43 , R b44 , R b45 , R b46 , and R b47 is independently
  • each R bl2 is independently selected from the group consisting of halo, alkyl,
  • haloalkyl and -OR b32 , wherein R b32 is hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • t is an integer from 0 to 6.
  • Embodiment 1-2 The compound of Embodiment 1-1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
  • A is 4- to 8-membered heterocycloalkyl
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • W is aryl or heteroaryl
  • X is -S(O)-, -S(0)2-, -S(0)NR b53 -, -C(S)-, -C(O)-, or -C(R bl3 ) 2- ;
  • each R bl3 is independently hydrogen, halo, alkyl, or haloalkyl
  • R bl is hydrogen, alkyl, or cycloalkyl
  • z is 0 or 1;
  • R b2 , R b3 , R b6 , R b7 , R b8 , R b9 , R bl °, and R bu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -CN, -OH, -NO2, -NH2, and -SO2NH2, wherein when one of R b6 and R b7 is alkyl, z is 1;
  • each R b4 is independently selected from the group consisting of halo, alkyl,
  • each R bl3 , R bl4 , R bl5 , R bl6 , and R b60 is independently hydrogen, alkyl
  • haloalkyl cycloalkyl, or halocycloalkyl
  • each R b5 is independently selected from the group consisting of halo, alkyl,
  • cycloalkyl heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
  • each R b65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R b63 , and R b64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each R bl7 , R bl8 , R b25 , R b26 , and R b27 is independently hydrogen, alkyl,
  • cycloalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl
  • each R bl9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
  • heterocycloalkyl, aryl, and heteroaryl of R b65 is independently unsubstituted or substituted with one or more substituents
  • halo 0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • each R b29 , R b30 , R b31 , R b43 , R b44 , R b45 , R b46 , and R b47 is independently
  • each R bl2 is independently selected from the group consisting of halo, alkyl,
  • haloalkyl and -OR b32 , wherein R b32 is hydrogen, alkyl, or haloalkyl;
  • n is an integer from 0 to 13;
  • n is an integer from 0 to 11;
  • t is an integer from 0 to 6.
  • Embodiment 1-3 The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (II- A):
  • p is an integer from 0 to 7;
  • Embodiment 1-4 The compound of any one of Embodiments 1-1 to 1-3, wherein the compound is of Formula (II-A-ii):
  • p is an integer from 0 to 7;
  • u is an integer from 0 to 5;
  • Embodiment 1-5 The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (P-B):
  • p is an integer from 0 to 7;
  • Y is -C(R b52 )2-,— S(0)r— , -0-, or -N(R b52 )-, wherein each R b52 is independently hydrogen or R b4 ; r is 0, 1, or 2; and
  • Embodiment 1-6 The compound of any one of Embodiments 1-1, 1-2, or 1-5, wherein the compound is of Formula (II-B-ii):
  • p is an integer from 0 to 7;
  • Y is -C(R b52 )2-,— S(0)r— , -0-, or -N(R b52 )-, wherein each R b52 is independently hydrogen or R b4 ; r is 0, 1, or 2; u is an integer from 0 to 5; and
  • Embodiment 1-7 The compound of Embodiment 1-5 or 1-6, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CH2-.
  • Embodiment 1-8 The compound of Embodiment 1-1 or 1-2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
  • Embodiment 1-9 The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment I- 10 The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
  • Embodiment 1-11 The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C9-Cio)bicyclic aryl.
  • Embodiment 1-12 The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C5-Cio)cycloalkyl.
  • Embodiment 1-14 The compound of any one of Embodiments 1-1 to 1-8, or 1-13, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
  • Embodiment 1-15 The compound of any one of Embodiments 1-1 to 1-4, 1-8, or I- 13, wherein the compound is of Formula (II-A-i):
  • R b4 , R b5 , R bl °, R bu , and R bl2 are as defined for Formula (II).
  • Embodiment 1-16 The compound of any one of Embodiments 1-1, 1-2, 1-5 to 1-8, or 1-13, wherein the compound is of Formula (II-B-i):
  • p is an integer from 0 to 7;
  • Y is -C(R b52 )2-— S(0)r— , -0-, or -N(R b52 )-, wherein each R b52 is independently hydrogen or R b4 ; r is 0, 1, or 2; u is an integer from 0 to 5; and
  • R b4 , R b5 , R bl °, R bu , and R bl2 are as defined for Formula (II).
  • Embodiment 1-17 The compound of any one of Embodiments 1-1 to 1-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R b5 is:
  • R b33 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,
  • Embodiment 1-18 The compound of Embodiment 1-17, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and R b34 is hydrogen.
  • Embodiment 1-20 The compound of Embodiment 1-19, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R b28 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
  • Embodiment 1-21 The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R bl and one R b4 , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
  • Embodiment 1-22 The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R bl and R b8 , together with the atoms to which they are attached, form a 3- to 6-membered
  • Embodiment 1-2 The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R bl and R b 10 , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
  • Embodiment 1-24 The compound of any one of Embodiments 1-1 to 1-23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
  • Embodiment 1-25 The compound of any one of Embodiments 1-1 to 1-23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
  • Embodiment 1-26 The compound of any one of Embodiments 1-1 to 1-23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CEb-
  • Embodiment 1-27 The compound of any one of Embodiments 1-1 to 1-14 or 1-17 to 1-26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  • Embodiment 1-28 The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-27, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
  • Embodiment 1-2 The compound of any one of Embodiments 1-3 to 1-7, 1-15, or 1-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.
  • Embodiment 1-30 The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R bl ° and R bu are independently selected from the group consisting of hydrogen, fluoro, -CN, unsubstituted methyl, and methyl substituted with one to three fluoro.
  • Embodiment 1-3 The compound of any one of Embodiments 1-1 to 1-30, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one R bl2 is chloro.
  • Embodiment 1-3 The compound of any one of Embodiments 1-1 to 1-3, 1-5, 1-7 to 1-14, or 1-17 to 1-30, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
  • Embodiment 1-3 The compound of any one of Embodiments 1-4, 1-6, 1-15, or I-
  • Embodiment 1-34 The compound of any one of Embodiments 1-1 to 1-32, wherein z is 0 or 1.
  • Embodiment 1-35 The compound of Embodiment 1-1 or 1-34, wherein the compound is:
  • Embodiment 1-36 The compound of Embodiment 1-1, wherein the compound is:
  • Embodiment 1-37 A pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-38 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 therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-39 The method of Embodiment 1-38, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-40 A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a
  • Embodiment 1-4 The method of Embodiment 1-40, wherein the disorder is cancer.
  • Embodiment 1-42 The method of Embodiment 1-41, 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 1-43 The method of Embodiment 1-40, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-44 The method of any one of Embodiments 1-40 to 1-43, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment 1-45 ETse of a compound of any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof.
  • Embodiment 1-46 The use of Embodiment 1-45, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-47 Use of a compound of any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
  • Embodiment 1-48 The use of Embodiment 1-47, wherein the disorder is cancer.
  • Embodiment 1-49 The use of Embodiment 1-48, 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 1-50 The use of Embodiment 1-47, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-51 The use of any one of Embodiments 1-47 to 1-50, wherein the disorder is associated with a mutation of K-Ras.
  • Embodiment 1-52 A compound according to any one of Embodiment 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
  • Embodiment 1-53 The compound for use of Embodiment 1-52, wherein the K-Ras protein is human K-Ras4b.
  • Embodiment 1-54 A compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
  • Embodiment 1-55 The compound for use of Embodiment 1-54, wherein the disorder is cancer.
  • Embodiment 1-56 The compound for use of Embodiment 1-55, 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 1-57 The compound for use of Embodiment 1-54, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
  • Embodiment 1-58 The compound for use of any one of Embodiments 1-54 to 1-57, wherein the disorder is associated with a mutation of K-Ras.
  • Example II- 1 Synthesis of tert-butyl (3-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate and tert-butyl (E)-(4-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate
  • Example II-2 Synthesis of tert-butyl (3-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamate and tert-butyl (E)-(4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)carbamate
  • Example II-4 Synthesis of tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamoyl)piperidine-l-carboxylate
  • Example II-5 Two Syntheses of (S,E)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4- chlorophenyl)sulfonyl)but-3-en-l-yl)piperidine-3-carboxamide
  • Route 1 In the first route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en- l-yl)carbamoyl)piperidine-l-carboxylate was combined with trifluoroacetic acid and dichloromethane, and that mixture stirred for 18 h from 0 °C to room temperature to remove the tert-butyloxycarbonyl (BOC) protecting group.
  • BOC tert-butyloxycarbonyl
  • Route 2 In the second route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3- en-l-yl)carbamoyl)piperidine-l-carboxylate is deprotected as described for Route 1, then the deprotected product combined with 5-chloro-2-methoxybenzoyl chloride, triethylamine, and dichloromethane, and the mixture stirred at room temperature for 4 h to produce (S,E)-l-(5- chloro-2-methoxybenzoyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)piperidine-3- carboxamide.
  • Example II-6 Synthesis of (S)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4- (trifluoromethyl)phenyl)sulfonyl)but-3-en-l-yl)piperidine-3-carboxamide
  • Example II-7 Synthesis of tert-butyl (E)-(4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamate
  • Example II-9 Synthesis of tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamoyl)pyrrolidine-l-carboxylate
  • Route 1 In the first route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamoyl)pyrrolidine-l-carboxylate was combined with trifluoroacetic acid and dichloromethane, and that mixture stirred for 18 h from 0 °C to room temperature to remove the tert-butyloxycarbonyl (BOC) protecting group.
  • BOC tert-butyloxycarbonyl
  • Route 2 In the second route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3- en-l-yl)carbamoyl)pyrrolidine-l-carboxylate was deprotected as described in Route 1.
  • LCMS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separations module and Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software.
  • the HPLC column used was an Agilent ZORBAX Eclipse XDB-C18 4.6x150, 3.5u Rapid Resol column with a mobile phase of water (0.1 % formic acid) / MeCN (0.1% formic acid) and a gradient of 5-95% MeCN over 5 minutes at a flow rate of 1 mL/min.
  • 6mins-0.5mL-min-Pos-only method (6 min): Performed on a Phenomenex Gemini 5mM C18 1 IqA, 50 x 3.0 mm column with a flow rate of lmL/minute using 0.1% v/v Formic acid in water [Eluent A]; MeCN [Eluent B]; Flow rate lmL/min;
  • Example 11-11 Covalent modification analysis using Matrix Assisted Laser
  • Target plate pretreatment Before each assay, the MALDI target plate (Bruker MTP 384 ground steel BC) was pre-treated by pipetting 1 m ⁇ of saturated sinapinic acid in acetonitrile (ACN) onto each spot. This may improve the uniformity of sample
  • 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 is set to x9 (1734 V), sample rate to 1 GS/s, smart beam parameter set: 3_medium is used, and the laser frequency is 66.7 Hz. Spectra were automatically collected using a custom AutoXecute method. Laser power is auto-adjusted using fuzzy control. The peak selection range was set to be between 20500 and 23000 Da. Peak evaluation uses half width parameter set to be smaller than 30 Da. Fuzzy control uses Proteins/Oligonucleotides protocol with minimum half width 1/6 times above threshold. Up to 1500 shots were collected in 500 shot steps. Dynamic termination was implemented to finish data collection when peak intensity is reaching value of 1200 [a.u.].
  • 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.
  • Compound 11-0096 (pyrrolidine) had greater reactivity than 11-0017 (piperidine).
  • the decreased reactivity of the other pyrrolidine compounds as evaluated by MALDI may be a result of precipitation of compound in aqueous MALDI matrix due to lower aqueous solubility. Their hydrophobicity may lead to greater cell permeability, and therefore better activity in cells.
  • Example 11-12 Compound labeling of GDP compared with GppNHp forms of KRAS4b protein
  • GppNHp nucleotide exchange One hundred fifty to 300 mM solution of GDP loaded protein in KRAS buffer (20 mM HEPES, 150 mM NaCl, 1 mM MgCk, 0.05 mM TCEP, pH 7.3) was prepared. Fifteen-hundred molar excess of 1 M ammonium sulfate in KRAS buffer was added and mixed gently by inverting tube. A 250 mM solution of GppNHp was prepared (150 molar excess of GppNHp to protein, on ice).
  • FIG. 1 A heat map comparing the covalent labeling of the two different proteins by selected compounds is provided in FIG. 1. This figure suggests that nucleotide loading (active GppNHp, compared to GDP-loaded KRAS4b) does not influence levels of KRAS4b 1-188 covalent labeling. This might suggest noncovalent docking to a different pocket of the protein than the Switch II pocket, which is available only in GDP -KRAS.
  • Example 11-13 Cellular uptake and stability in cells
  • MiaPaCa-2 cells were plated at 2xl0 5 per dish onto 10 cm dishes, and allowed to attach overnight. Cells were treated for 72 h with DMSO or 10 mM to 50 pM compound II- 0017 (compound added once). Compound 11-0017 appeared to be active at 20 pM
  • 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:
  • FIG. 4 is a heat map of the ICso values for selected compounds in KRAS G12 mutants and control MEF lines.
  • Cells expressing oncogenic mutants KRAS4b G12V and KRAS4b Q61R show higher sensitivity to these compounds, compared with cells driven by HRAS WT or Myr-KRAS4b G12D/C185S (negative control).
  • Compound 11-0017 was evaluated in a Western blot analysis of KRAS total protein level. Two cancer cell lines were used, HupT4 (pancreas cancer line bearing KRAS G12V mutant) and H1792 (lung adenocarcinoma bearing G12C mutant). KRAS protein level was evaluated by Western blot after 72 h treatment with the compound, using three different anti- RAS antibodies (as indicated in FIG. 5A). MEK total protein level was used as a loading control. 11-0017 caused dose-dependent decreased level of KRAS protein in both cell lines.
  • Alexa Fluor 647-azide was used to detect compound 11-0144 covalently attached to KRAS4b G12D purified from cells on Flag Ml agarose, via the ligation or“click”
  • FIG. 6 depicts gel images of the Alexa Fluor 647 signal (negative from whole cells lysates that were not subjected to the click conjugation reaction) and positive for pull-down (Pd) of Flag-KRAS4b from HEK293 expressing KRAS4b G12V treated with 11-0144, after click-reaction has been performed.
  • LMW low molecular weight standards.
  • Cells are rinsed thrice with ice-cold PBS and then are lysed on ice with ice-cold TNE buffer supplemented with Halt protease and phosphatase inhibitors (Thermo Scientific). This is then centrifuged at 15,000 for 15 minutes to collect whole-cell lysates. Protein concentration is measured with the BCA protein assay (Pierce). Thirty micrograms of total protein per sample is loaded into 4%-l2% NuPAGE Bis-Tris gradient gels (Life
  • VDF polyvinylidene difluoride
  • 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 -ART (Cell Signaling Technology 2920).
  • Vinculin rabbit anti-vinculin, Cell Signaling Technology 4650
  • Primary antibodies are detected with fluorescence-conjugated (LI-COR) secondary antibodies.
  • cells are seeded at 2xl0 5 onto lO-cm Petri dishes and allowed to grow for 24 h. Compounds are added to the medium to a final concentration 10 - 30 mM for 72h. Cells are rinsed three times with ice-cold PBS, then digitonin [300 m ⁇ of 190 mg/ml in lysis buffer (PBS containing 75 mM KC1, 250 mM sucrose and Halt protease and phosphatase inhibitors (Thermo)] is added for 10 min on ice. Cells are then scraped gently and centrifuged 10 min at 12,000 at 4 °C.
  • lysis buffer PBS containing 75 mM KC1, 250 mM sucrose and Halt protease and phosphatase inhibitors (Thermo)
  • the supernatant (cytosolic fraction) is removed, and the remaining pellet (membrane fraction) is resuspended in 100 m ⁇ of TNE lysis buffer (25 mM HEPES buffer containing 150 mM NaCl, 5 mM MgCl 2 , 1% SDS, 10% glycerol, 2.5 mM EDTA, supplemented with Halt protease and phosphatase inhibitors) and allowed to incubate for 30 min before processing with standard immunoblot protocol.
  • TNE lysis buffer 25 mM HEPES buffer containing 150 mM NaCl, 5 mM MgCl 2 , 1% SDS, 10% glycerol, 2.5 mM EDTA, supplemented with Halt protease and phosphatase inhibitors
  • mouse monoclonal anti-KRAS (Sigma WH0003845M1, clone 3B10-2F2)
  • mouse anti-RAS Thermo 1862335
  • mouse anti-MEKl/2 Cell Signaling Technology 4694
  • rabbit anti-Na,K-ATPase Cell Signaling Technology 3010
  • Example 11-18 Tumor Xenograft
  • Human pancreas or lung adenocarcinoma cell lines are obtained from the American Type Culture Collection and cultured according to the cell supplier’s protocol, for a maximum of four passages before use. Cells are harvested at 70-80% confluence, washed with phosphate buffered saline, suspended in phosphate buffered saline, and implanted subcutaneously at 5 x 10 6 cells/0.2 mL into NCr nu/nu athymic mice, obtained from Charles River. Frederick National Laboratory for Cancer Research is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals.
  • mice 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.
  • mice Compounds are injected into the tail veins of the mice, at 100 pmol/kg body weight, 3 times per week for 4 weeks. Control groups are treated with saline. Mice are weighed, and tumors are measured 2 times per week. Tumor volumes in mm 3 are estimated by the formula (p/2 x length c width 2 ). Mice are euthanized almost immediately after the last treatment. Blood is collected under isoflurane anesthesia. Tumors are removed and frozen immediately for biochemical analysis.

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Abstract

Provided herein are compounds comprising a vinyl sulfone 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 SULFONE MOIETY
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 62/659,602, filed April 18, 2018, the disclosure of which is 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 K-Ras protein, and more specifically to inhibitors with a vinyl sulfone 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 the RAS/MAPK signaling pathway. K-Ras is a GTPase that acts as a molecular switch, flipping between an active GTP-bound form and an inactive GDP -bound form. The K-Ras protein plays a crucial role in tissue signaling, and is involved in cell proliferation, cell differentiation, and apoptosis.
Activating mutations in KRAS are common in many different human cancers. Thus, what is needed are effective inhibitors of K-Ras, and effective inhibitors of the post-translational processing of KRAS that produces a mature fully-processed K-Ras protein.
BRIEF SUMMARY
[0005] In one aspect, provided herein is a compound of Formula (I):
Figure imgf000004_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0, 1, or 2;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NRbl3Rbl4, -ORb15, -S02Rbl6, and -S02NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1; each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -N02, -CN, -S02NH2,
— NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; and each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or Rb2 and Rb3 together form =0; or Rb6 and Rbl, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo; or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or two to four Rb4, 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; each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -N02, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21; 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, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63, -S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rbl7 Rbl8 Rbl9 Rb20 Rb21 Rb22 Rb23 Rb24 Rb25 Rb26 Rb27 Rb54 Rb55 RbS6, Rb57 Rb58^ Rb59^ Rb6i^ Rb62^ Rb63^ and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7,
RM8, RbW Rb22^ Rb23^ Rb24^ Rb25^ Rb26^ Rb27^ and Rb28^ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31;
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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl;
each Rbl2 is independently selected from the group consisting of halo, alkyl,
haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
[0006] In some variations of the compound of Formula (I), or a stereoisomer or
pharmaceutically acceptable salt thereof, A is 5- or 6-membered heterocycloalkyl.
[0007] In one aspect, the compound of Formula (I) is a compound of Formula (II):
Figure imgf000007_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
z is 0 or 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NRbl3Rbl4, -ORb15, -S02Rbl6, and -S02NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1; each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -N02, -CN, -S02NH2,
— NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; and
each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or Rb2 and Rb3 together form =0; or Rb6 and Rbl, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo; or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo; or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo; or two to four Rb4, 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; each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -N02, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21; 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, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63, -S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rbl7 Rbl8 Rbl9 Rb20 Rb21 Rb22 Rb23 Rb24 Rb25 Rb26 Rb27 Rb54 Rb55 RbS6, Rb57 Rb58^ Rb59^ Rb6i^ Rb62^ Rb63^ and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7,
RM8, RbW Rb22^ Rb23^ Rb24^ Rb25^ Rb26^ Rb27^ and Rb28^ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31;
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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl;
each Rbl2 is independently selected from the group consisting of halo, alkyl,
haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
[0008] In some variations of the compound of Formula (I) or Formula (II), or a
stereoisomer or pharmaceutically acceptable salt thereof, A is 5- or 6-membered
heterocycloalkyl. [0009] In some variations, the compound of Formula (II) is a compound of Formula (P-A):
Figure imgf000010_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; and B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II).
[0010] In other variations, the compound of Formula (II) is a compound is of Formula (II- A-ii):
Figure imgf000010_0002
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; u is an integer from 0 to 5; and B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
[0011] In some variations, the compound of Formula (II) is a compound of Formula (P-B):
Figure imgf000010_0003
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; Y is -C(Rb52)2-, -S(0)— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; and B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II). [0012] In certain variations, the compound of Formula (II) is a compound of Formula (II- B-ii):
Figure imgf000011_0001
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; Y is -C(Rb52)2-, -S(0)— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; u is an integer from 0 to 5; and B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
[0013] In certain variations of the compound of Formula (II-B) or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, Y is -CH2-. In some variations of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (II- B), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the
heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other variations, 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 further variations, B is (C9-Cio)bicyclic aryl. In some variations, B is (C5-Cio)cycloalkyl.
[0014] In certain variations, the compound of Formula (II-B) is a compound of Formula
(II-A-i):
Figure imgf000011_0002
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; u is an integer from 0 to 5; and X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
[0015] In some variations, the compound of Formula (II-B) is a compound of Formula (II- B-i):
Figure imgf000012_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; Y is -C(Rb52)2-, -S(0)— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; u is an integer from 0 to 5; and X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
[0016] In some variations of the compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 is:
Figure imgf000012_0002
wherein:
Rb33 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, -ORb36, -SFs, and -NRb37Rb38; 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, -ORb39,
-NRb48Rb49, -NRb50C(O)Rb51, 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 Rb34 and Rb35 are 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, -ORb40, and -NRb41Rb42; 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 Rb34 and one Rb35 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 Rb36, Rb37, Rb38, Rb39, Rb40, Rb41, Rb42, Rb48, Rb49, Rb50, and Rb51 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
[0017] In some variations of the compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 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 Rb28.
[0018] In some variations of the compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(0)2- In other variations, X is— C(O)— . In certain variations, X is -CFh- In some variations, n is 1 or 2. In other variations, m is 0 In certain variations, p is 0
[0019] In some variations of the compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rbl2 is chloro.
[0020] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some variations, the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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 (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient. In some variations, the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer 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 (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some variations, the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof. [0023] In yet a further aspect, provided herein is the use of a compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof. In some variations, the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
[0024] In another aspect, provided herein is the use of a compound of Formula (I) or Formula (II), or a stereoisomer or 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 (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
[0025] In still a further aspect, provided herein is a compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof. In some variations, the compound of Formula (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof.
[0026] In yet another aspect, provided herein is a compound of Formula (I) or Formula (II), or a stereoisomer or 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 (I) or Formula (II) is a compound of Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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, such as treatments of disorders including cancer, 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. l is a heat map comparing the covalent labeling of the proteins GppNHp-K- Ras4b and GDP-K-Ras4b different proteins by selected compounds described herein.
[0030] FIG. 2 is a graph of uptake of compound 11-0017 by MiaPaCa-2 pancreas carcinoma cells over time.
[0031] FIG. 3 depicts images of MiaPaCa-2 cells pancreas carcinoma cells incubated with dimethyl sulfoxide (DMSO) or different concentrations of compound 11-0017 for 72 h.
Activity in cells is indicated by growth arrest.
[0032] FIG. 4 is a heat map of ICso values for selected compounds as measured in different mouse embryonic fibroblast cells (MEF).
[0033] FIG. 5 A depicts Western blot analysis of compound 11-0017 taken up by two cancer cell lines, HupT4 (pancreas cancer line bearing K-Ras G12V mutant) and H1792 (lung adenocarcinoma bearing G12C mutant).
[0034] FIG. 5B depicts images of cell proliferation in the presence of dimethyl sulfoxide (DMSO, control) or different amounts of compound 11-0017 in the H1792 lung
adenocarcinoma cell line.
[0035] FIG. 6 depicts gel images of the Alexa Fluor 647 signal (negative from whole cells lysates that were not subjected to the click conjugation reaction) and positive for pull-down (Pd) of Flag-K-Ras4b from HEK293 expressing K-Ras4b G12V treated with 11-0144. LMW = low molecular weight standards.
DETAILED DESCRIPTION
[0036] 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.
[0037] Provided herein is a compound, such as a compound of Formula (I), (II), (II- A), (II- A-i), (II-A-ii), (P-B), (II-B-i), or (II-B-ii), or a stereoisomer or 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 KRAS that produces a K-Ras protein, such as K-Ras4b. For example, in some embodiments, this compound may block the famesylation of a of the newly synthesized K-Ras, preventing its C-terminal processing. In other embodiments, this compound or stereoisomer or pharmaceutically acceptable salt thereof may be administered to a subject in need thereof, for example in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. 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 of KRAS. The disorder may be, for example, a disorder associated with a mutation in a K-Ras protein. In some embodiments, the compound inhibits K-Ras, or decreases the level of K-Ras, or inhibits the post-translational processing of KRAS to produce a K-Ras protein, such as K-Ras4b. The compounds, compositions comprising said compounds, and methods of using said
compounds and compositions of the present disclosure are described in greater detail below.
I. Compounds of Formula (I)
[0038] Provided herein is a compound of Formula (I):
Figure imgf000017_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl; X is -S(O)-, -S(0)2- -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-; each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0, 1, or 2;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NRbl3Rb14, -ORb15, -S02Rb16, and -SO2NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1; each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6; 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, -S04H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(O)- alkyl, -NHC(0)0-alkyl,-NHC(0)0H, -NHOH, -OH, -O-alkyl, -O- haloalkyl, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or Rb2 and Rb3 together form =0; or Rb6 and Rbl, together with the atoms to which they are attached, form a heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one or more halo;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb4, 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;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21;
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, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63, -S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rbl7 Rbl8 Rbl9 Rb20 Rb21 Rb22 Rb23 Rb24 Rb25 Rb26 Rb27 Rb54 Rb55 Rb56, Rb57, Rb58, Rb59, Rb61, Rb62, Rb63, and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb22, Rb23, Rb24, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31;
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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl;
each Rbl2 is independently selected from the group consisting of -CN, -NIL·,
-NH(alkyl), -COOH, -C(0)0-alkyl, -COML·, -NO2, -SH, -S-alkyl, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHS02H,-NHC(0)H, -NHC(0)-alkyl, -NHC(0)0-alkyl,-NHC(0)0H, -NHOH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, alkyl, haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and t is an integer from 0 to 6.
[0039] In some embodiments, the compound of Formula (I) is a compound of Formula (II):
Figure imgf000021_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0 or 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, — NRbl3Rb14, -ORb15, -S02Rb16, and -SO2NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1; each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2,
-NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6; 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, -SC H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(O)- alkyl, -NHC(0)0-alkyl,-NHC(0)0H, -NHOH, -OH, -O-alkyl, -O- haloalkyl, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or Rb2 and Rb3 together form =0;
or Rb6 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one or more halo;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb4, 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;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21; 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, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58,
-SOzRb59, and Rb28, wherein each Rb28 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, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63,
-SOzRb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rbl7 Rbl8 Rbl9 Rb20 Rb21 Rb22 Rb23 Rb24 Rb25 Rb26 Rb27 Rb54 Rb55 Rb56, RbS7 Rbs^ Rbs^ Rb6i^ Rb62^ Rb63^ and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb22, Rb23, Rb24, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -0Rb31; 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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl;
each Rbl2 is independently selected from the group consisting of -CN, -NH2,
-NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHS02H,-NHC(0)H, -NHC(0)-alkyl, -NHC(0)0-alkyl,-NHC(0)0H, -NHOH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, alkyl, haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
[0040] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rb4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6, 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, -CCh, -CBn, -CF3, -CI3, -CH2CI, -CFhBr, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -OH, -COOH, -SH, -SO3H, -S04H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHC(0)-alkyl, -NHC(0)0-alkyl, -NHOH, -OCCh, -OCBr3, -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)cycloalkyl),
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).
[0041] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rbl2 is independently selected from the group consisting of-CN, -NH2, -NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SO3H, -S04H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2.
NHC(0)NH2, -NHS02H,-NHC(0)H, -NHC(0)-alkyl, -NHC(0)0-alkyl,-NHC(0)0H,
NHOH, -CCh, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, CHF2, -CHI2, -OCCh, -OCBr3,-OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I,
-OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -CONH2, halo ,-O-alkyl, -OH, 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)cycloalkyl), 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).
[0042] In some embodiments of the compound of Formula (II):
Figure imgf000025_0001
or a stereoisomer or pharmaceutically acceptable salt thereof:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-; each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0 or 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NRbl3Rb14, -ORb15, -S02Rb16, and -SO2NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1; each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NCte, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rb16, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or Rb2 and Rb3 together form =0;
or Rb6 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb4, 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;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NCte, -CN,
-SCteNRb54Rb55, -NRbl7Rb18, -ORb19, -SCteRb20, =0, and -SRb21;
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, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58,
-SOzRb59, and Rb28, wherein each Rb28 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, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63,
-S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rbl7 Rbl8 Rbl9 Rb20 Rb21 Rb22 Rb23 Rb24 Rb25 Rb26 Rb27 Rb54 Rb55 RbS6, RbS7 Rbs^ Rbs^ Rb6i^ Rb62^ Rb63^ and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb22, Rb23, Rb24, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31; wherein each aryl, heteroaryl, alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl; each Rbl2 is independently selected from the group consisting of halo, alkyl, haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
[0043] In certain embodiments of the compound of Formula (II):
Figure imgf000028_0001
or a stereoisomer or pharmaceutically acceptable salt thereof:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, or cycloalkyl;
z is 0 or 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -CN, -OH, -NO2, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1;
each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; and each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
or Rb2 and Rb3 together form =0;
or Rb6 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl;
or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl;
or two to four Rb4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NCte, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21;
wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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 Rb28, wherein each Rb28 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 halo, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63,
-S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, a irryyli, o orr h neetreerrooaarryyli;, each Rb20, Rb21, Rb22, Rb23 ub24 T>b54 ub55 ub56 ub57 u b58 ub59 ub61 u b62 rv , rv , rv , rv , rv , rv , rv , rv , rv ,
Rb63, and Rb64 is indepoendentlyv hyydroggen, alkyyl, haloalkyyl,. cyvcloalkyv l, or halocycloalkyl; each Rbl7, Rbl8, Rb25, Rb26, and Rb27 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rbl9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, R 8, Rbl9, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl of Rb65 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,
-NRb29Rb3°, -SFs, and -ORb31; 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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl; each Rbl2 is independently selected from the group consisting of halo, alkyl, haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
[0044] In certain embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or 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.
[0045] In some embodiments of the compound of Formula (I) or Formula (II), or a
stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000031_0001
Figure imgf000031_0002
12.
[0046] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, Rbl is hydrogen, alkyl, halolkyl, cycloalkyl, or halocycloalkyl. In some embodiments, Rbl is hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocydoalkyl. In certain embodiments, Rbl is hydrogen, (Ci-Ce)alkyl, or (C3-C6)cydoalkyl. In some embodiments, Rbl is hydrogen. In other embodiments, Rbl is (Ci-C6)alkyl. For example, in some embodiments, Rbl is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, Rbl is (C3-C6)cydoalkyl. For example, in some embodiments, Rbl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0047] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NCte, -NRbl3Rb14, -ORb15, -S02Rb16, and -SO2NH2; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1. In some embodiments, when one of Rb6 and Rb7 is alkyl or haloalkyl, z is 1. In certain embodiments, when one or both of Rb6 and Rb7 are independently alkyl or haloalkyl, z is 1.
In some embodiments, when both Rb6 and Rb7 are independently alkyl, z is 0 or 1. In certain embodiments, when both Rb6 and Rb7 are independently alkyl or haloalkyl, z is 0 or 1. In some embodiments, each Rbl3, Rbl4, Rbl5, and Rbl6 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl. In certain embodiments, each Rbl3, Rbl4, Rbl5, and Rbl6 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each Rbl3, Rbl4, Rbl5, and Rbl6 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 some embodiments, each Rbl3, Rbl4, Rbl5, and Rbl6 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)halocydoalkyl.
[0048] In some embodiments, Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NCte,
-CN, -OH, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1; or Rb2 and Rb3 together form =0. In some embodiments, Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1; or Rb2 and Rb3 together form =0. In certain embodiments, Rb2, Rb3, Rb6, Rb7,
Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, chloro, fluoro, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and -OH, wherein when one of Rb6 and Rb7 is alkyl, z is 1; or Rb2 and Rb3 together form =0. In certain embodiments of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, Rb2 and Rb3 together form =0, and Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -NCte, -CN, -OH, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1. In certain embodiments, Rb2 and Rb3 together form =0, and Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, chloro, fluoro, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and - OH, wherein when one of Rb6 and Rb7 is alkyl, z is 1. In still further embodiments, Rb2 and Rb3 together form =0; Rb6, Rb7, Rb8, and Rb9 are each hydrogen; and Rbl° and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -NO2, - CN, -OH, -NH2, and -SO2NH2. In certain embodiments, Rb2 and Rb3 together form =0; Rb6, Rb , Rb8, and Rb9 are each hydrogen; and Rbl° and Rbu are independently selected from the group consisting of hydrogen, halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -NO2, -CN, -OH, -NH2, and -SO2NH2. In some embodiments, Rb2 and Rb3 together form =0; Rb6, Rb7, Rb8, and Rb9 are each hydrogen; and Rbl° and Rbu are independently selected from the group consisting of hydrogen, fluoro, chloro, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and -OH. In some embodiments, one of Rbl° and Rbu is hydrogen. In some embodiments, Rbl° and Rbu are both hydrogen. In some embodiments, both Rb6 and Rb7 are alkyl, and z is 0 or 1. In some embodiments, Rb6 and Rb7 are independently alkyl or haloalkyl, and z is 0 or 1.
[0049] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, Rb6 and Rbl, 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 certain embodiments, Rb6 and Rbl, 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. For example, in some embodiments,
Figure imgf000033_0001
[0050] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, Rbl° and Rbl, 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 certain embodiments, Rbl° and Rbl, together with the atoms to which they are attached, form a 3- to lO-membered
heterocycloalkyl, or a 3- to 8-membered heterocycloalkyl, or a 3- to 6-membered
heterocycloalkyl, or a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the
heterocycloalkyl is unsubstituted.
[0051] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, Rb8 and Rbl, 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 certain embodiments, Rb8 and Rbl, together with the atoms to which they are attached, form a 3- to lO-membered
heterocycloalkyl, or a 3- to 8-membered heterocycloalkyl, or a 3- to 6-membered
heterocycloalkyl, or a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the
heterocycloalkyl is unsubstituted.
[0052] In some embodiments of the compound of Formula (I) or Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, two to four of Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo. In some embodiments , two to four of Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are attached, form a 3- to lO-membered heterocycloalkyl, or a 3- to 8-membered heterocycloalkyl, or a 3- to 6-membered heterocycloalkyl, or a 4- 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, two to four of Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are attached, form a 5- to lO-membered heteroaryl, or a 5- to 8-membered heteroaryl, or a 5- to 6-membered heteroaryl, wherein the heteroaryl is unsubstituted or substituted with one or more halo. In some embodiments, the heteroaryl is unsubstituted. When two or three of Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo, the remaining one or two of Rb2, Rb3, Rb6, and Rb7 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, -NRbl3Rb14, -ORb15, -S02Rb16, and -SO2NH2; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1.
[0053] "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.
[0054] “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,
-CHCh, -CCh, -CH2CHFCI, -CHFCH3, -CH2Br, and -CH2CHF CH2CH2Br .
[0055] “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.
[0056] “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.
[0057] “Alkynoxy”, as used herein, refers to a -O-alkynyl moiety, wherein alkynyl is as described above.
[0058] “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-C5)cydoalkyl). 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.
[0059] “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.
[0060] "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 of the fused ring for which valency permits.
[0061] "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, 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). 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 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.
[0062] “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). 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 1 to 3 ring heteroatoms independently selected from N, O, and S.
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.
[0063] “Haloheterocycloalkyl”, as used herein, refers to a heterocycloalkyl group substituted with one or more halo, which may be selected independently. Thus,
haloeheterocycloalkyl includes heterocycloalkyl substituted with one or more halo independently selected from the group consisting of fluoro, chloro, iodo, and bromo.
[0064] “Halo” or“halogen” includes bromo, chloro, fluoro, and iodo.
[0065] 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, or I; an oxygen atom in a hydroxyl group; a nitrogen atom in an amino group; or an oxygen atom in a sulfur dioxide group.
[0066] 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, C 1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0067] In some embodiments, the compound of Formula (II) is a compound of Formula (II-
A):
Figure imgf000039_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; and
B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II).
[0068] In some embodiments of the compound of Formula (P-A), or a stereoisomer or 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.
[0069] In some embodiments, the compound of Formula (II) is a compound of Formula (II- B):
Figure imgf000039_0002
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; and
B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II). [0070] In some embodiments of the compound of Formula (P-B), or a stereoisomer or 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.
[0071] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is aryl or heteroaryl. In some embodiments, W is (C6-Cio)aryl. In certain embodiments, W is 5- to 8-membered heteroaryl. In certain embodiments, W is 5- to 7-membered heteroaryl. In some embodiments, W is 5-, 6-, or 7-membered heteroaryl. In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is 5- to lO-membered heteroaryl, wherein the heteroaryl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, W is 5- or 6-membered heteroaryl, wherein the heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, W is 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, W is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl.
[0072] In some embodiments of the compound of Formula (I), Formula (II), Formula (II-
A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof, W 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 (I), Formula (II), Formula (II- A), or Formula (II-
B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is:
Figure imgf000041_0001
[0073] In other embodiments of the compound of Formula (I), Formula (II), Formula (II-
A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is aryl. For example, in some embodiments, W 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 (II), Formula (II- A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is phenyl or naphthyl. In some embodiments, W 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 (I), Formula (II), Formula (II- A), or Formula (II-
B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is:
Figure imgf000041_0002
[0074] It should be understood that for embodiments described herein, W may be unsubstituted or substituted with one to six Rbl2 as described in Formula (I), Formula (II), Formula (P-A), and Formula (P-B), as valency allows. For example, in some embodiments,
Figure imgf000042_0001
, , , wherein t is an integer from 0 to 5.
[0075] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof, t is an integer from 0 to 6. In some embodiments, t is an integer from 0 to 5. In other embodiments, t is an integer from 0 to 4. In still further embodiments, t is an integer from 0 to 3. In certain embodiments, t is 0, 1, or 2. In other embodiments, t is an integer from 1 to 6, or from 2 to 6, or from 3 to 6, or from 3 to 5, or from 2 to 4. In certain embodiments, t is 0. In other embodiments, t is 1. In some embodiments, t is 2. In still other embodiments, t is 3. In still further embodiments, t is 4. In some embodiments, t is 5. In certain embodiments, t is 6.
[0076] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof, W is phenyl, and t is an integer from 0 to 5. In some embodiments of the compound of Formula (I), Formula (II), Formula (P-A), or Formula (P-B), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000042_0002
, wherein u is an integer from 0 to 5.
[0077] In some embodiments, the compound of Formula (II) is a compound of Formula (II- A-ii):
Figure imgf000043_0001
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and
B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
[0078] In some embodiments of the compound of Formula (II-A-ii), or a stereoisomer or 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. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
[0079] In some embodiments, the compound of Formula (II) is a compound of Formula (II- B-ii):
Figure imgf000043_0002
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -O-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2;
u is an integer from 0 to 5; and
B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
[0080] In some embodiments of the compound of Formula (II-B-ii), or a stereoisomer or 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. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
[0081] In certain embodiments of the compound of Formula (II-B) or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, Y is -C(Rb52)2-, wherein each Rb52 is independently hydrogen or Rb4. In certain embodiments, Y is -CFh- In other embodiments, Y is -CHRb4-. In some embodiments, Y is -C(Rb4)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(Rb52)-, wherein Rb52 is hydrogen or Rb4. For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NRb4-.
[0082] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (II-B), or Formula (II-B-ii), or a stereoisomer or
pharmaceutically acceptable salt thereof, B is heteroaryl, cycloalkyl, or heterocycloalkyl. In some embodiments, B is 5- to lO-membered heteroaryl, or 5- to lO-membered
heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S. 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. [0083] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
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 (I), Formula (II), Formula (P-A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or 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 (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (II-B), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is:
Figure imgf000045_0001
[0084] In other embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
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 10- 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 lO-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 (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II- B-ii), or a stereoisomer or 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 (I), Formula (II), Formula (II- A), Formula (II-A- ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is:
Figure imgf000046_0001
Figure imgf000047_0002
[0085] In other embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
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 (I), Formula (II), Formula (P-A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is phenyl or napthyl. 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 (I), Formula (II), Formula (P-A), Formula (II-A-ii), Formula (P-B), or Formula (II- B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is:
Figure imgf000047_0001
[0086] In still further embodiments of the compound of Formula (I), Formula (II), Formula (II-A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is cycloalkyl. For example, in some
embodiments, B is (C3-Cio)cycloalkyl. In certain embodiments, B is (C5-Cio)cycloalkyl. In other embodiments, B is (C5-C7)cycloalkyl. In still other embodiments, B is (Cs- Cio)cycloalkyl. In some embodiments, B is C3-cycloalkyl, C4-cycloalkyl, Cs-cycloalkyl, C6- cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or C 10-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 (I), Formula (II), Formula (II-A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or 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 (I), Formula (II), Formula (P-A), Formula (II-A-ii), Formula (P-B), and Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is:
Figure imgf000048_0001
[0087] It should be understood that for embodiments described herein, B may be unsubstituted or substituted with one to eleven Rb5 as described in Formula (I), Formula (II), Formula (P-A), Formula (II-A-ii), Formula (P-B), and Formula (II-B-ii), as valency allows.
[0088] For example, in some embodiments, B is
Figure imgf000048_0002
, , , wherein n is an integer from
0 to 5.
[0089] In other embodiments, B is
Figure imgf000048_0004
as described above, and
Figure imgf000048_0003
*s
Figure imgf000048_0005
, wherein n is an integer from 0 to 11.
[0090] In still other embodiments B is
Figure imgf000048_0007
, as described above, and
Figure imgf000048_0006
is
Figure imgf000048_0008
, 5) are present, it should be understood that they may be optionally different unless otherwise indicated. [0091] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
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.
[0092] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
pharmaceutically acceptable salt thereof, B is phenyl, and n is an integer from 0 to 5. Thus, for example, in some embodiments of the compound of Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000049_0001
Figure imgf000049_0002
. When multiple instances of a substituent (for example, Rb5) are present, it should be understood that they may be optionally different unless otherwise indicated.
[0093] In some embodiments, of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
pharmaceutically acceptable salt thereof,
Figure imgf000050_0001
[0094] In some embodiments, the compound of Formula (II) is a compound of Formula (II-
A-i):
Figure imgf000050_0002
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
u is an integer from 0 to 5; and
X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
[0095] In some embodiments of the compound of Formula (I), Formula (II-A-i), or a stereoisomer or 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. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
[0096] In some embodiments of the compound of Formula (I), Formula (P-A), Formula (II- A-i), or Formula (II-A-ii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000051_0002
[0097] In some embodiments, the compound of Formula (II) is a compound of Formula (II- B-i):
Figure imgf000051_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4;
r is 0, 1, or 2;
u is an integer from 0 to 5; and
X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
[0098] In certain embodiments of the compound of Formula (I), Formula (II-B-i), or a stereoisomer or pharmaceutically acceptable salt thereof, Y is -C(Rb52)2-, wherein each Rb52 is independently hydrogen or Rb4. In certain embodiments, Y is -CFh- In other
embodiments, Y is -CHRb4-. In some embodiments, Y is -C(Rb4)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 -O-. In other embodiments, Y is -N(Rb52)-, wherein Rb52 is hydrogen or Rb4. For example, in certain embodiments, Y is -NH-. In other embodiments, Y is -NRb4-.
In some embodiments of the compound of Formula (II-B-i), or a stereoisomer or
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. In some embodiments, u is 0. In other embodiments, u is 1. In still further embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
[0099] In some embodiments of the compound of Formula (I), Formula (P-B), Formula (II- B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000052_0001
integer from 0 to 6. In other
embodiments,
Figure imgf000052_0002
integer from 0 to 6.
[0100] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
pharmaceutically acceptable salt thereof,
Figure imgf000052_0003
Figure imgf000052_0004
Figure imgf000053_0001
some embodiments,
Figure imgf000053_0002
When multiple instances of a substituent
(for example, Rbl2) are present, it should be understood that they may be optionally different unless otherwise indicated.
[0101] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rbl2 is independently selected from the group consisting of halo, alkyl, haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl. In certain embodiments, each Rbl2 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In some embodiments, each Rbl2 is independently fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2,
-CH2F, -CHF2, -CFs, -CH2CI, -CHCI2, -CCh, -CH2Br, -CHBr2, -CBr3, -CH2I, -CHFI2, -CI3, -OCH2CI, -OCHCI2, -OCCh, -OCH2Br, -OCHBr2, -OCBr3, -OCH2I, -OCHFI2, -OCI3, -OCH2F, -OCHF2, or -OCF3. In certain embodiments, each Rbl2 is independently fluoro, chloro, -OCH3, or -CF3. In some embodiments, each Rbl2 is independently fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, or -OCF3. In certain embodiments, each Rbl2 is independently fluoro, chloro, -OCH3, or -CF3.
[0102] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (P-B), or Formula (II-B-i), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000054_0001
Figure imgf000054_0002
[0103] In some embodiments of the compound of Formula (II-A-ii) or Formula (II-B-ii), or
a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000054_0003
Figure imgf000054_0004
[0104] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rb4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -Mb, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo. In some embodiments, each Rb4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rb16, wherein each alkyl, cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with one or more halo. In some embodiments, each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl. In certain embodiments, each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 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 some embodiments, each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, and (C3- C6)halocycloalkyl.
[0105] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rb4 is independently selected from the group consisting of 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, and -S02-(Ci-C6)alkyl. In some embodiments, each Rb4 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 Rb4 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 Rb4 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 Rb4 is fluoro, chloro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2, or -CF3.
[0106] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii) or a stereoisomer or pharmaceutically acceptable salt thereof, two to four Rb4, 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 Rb4, 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 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted. 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 Rb4, 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 Rb4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo.
[0107] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rb5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN, -S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21. In some embodiments, one or more Rb5 is independently selected from the group consisting of halo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro or chloro; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3-C6)cycloalkyl unsubstituted or substituted with one or more fluoro or chloro; -0-(C2-C4)alkynyl; and (Ci- C6)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, -NRb26Rb27, and -CN. In certain embodiments, one or more Rb5 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
Rb5 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 certain embodiments, one or more Rb5 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 Rb5 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, -OCH2F, -OCHF2, -OCF3, -NO2, phenyl, =0, -SO2NH2, -CN, cyclopropyl, cyclohexyl, and -OCH2CCH. In some embodiments, at least one Rb5 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, -CCh, -CH2Br, -CHBr2, -CBn, -CH2I, -CHFI2, -CI3, -OCH2CI, -OCHCh, -OCCh, -OCH2B1-, -OCHBn, -OCBn, -OCH2I, -OCHFI2, -OCI3, -OCH2F, -OCHF2, -OCF3, -NO2, phenyl, =0, -SO2NH2, -CN, cyclopropyl, cyclohexyl, and -OCH2CCH.
[0108] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 is alkyl, wherein each alkyl is independently unsubstituted or substituted with one or more
substituents independently selected from the group consisting of halo, -ORb25, =0,
-NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63, -S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each
Rb65 is independently (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In certain embodiments, at least one Rb5 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, -ORb25, =0, -NRb26Rb27, -CN, and -SFs. In some embodiments, the alkyl is (Ci-Ci2)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In other embodiments, the alkyl is (Ci-C8)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In further embodiments, the alkyl is (Ci- C6)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In still other embodiments, the alkyl is (Ci-C4)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In some embodiments, at least one Rb5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, difluoromethyl, or fluoromethyl.
[0109] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 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, -ORb22, =0,
-NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain
embodiments, each Rb28 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, Rb28 is unsubstituted alkyl. In some embodiments, Rb28 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rb28 is alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkynyl, cycloalkyl,
heterocycloalkyl, -NRb29Rb3°, -ORb31, and -SFs. In certain embodiments, Rb28 is (Ci- C6)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkynyl, cycloalkyl, heterocycloalkyl,
-NRb29Rb3°, -ORb31, and -SFs. In some embodiments, Rb28 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRb29Rb3°, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In certain embodiments, Rb28 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
[0110] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 is cycloalkyl, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rb28 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 Rb5 is cycloalkyl, wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, halo, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, and -SOzRb59. In some embodiments, at least one Rb5 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, -NRb23Rb24, -CN, and -SFs. In some embodiments, at least one Rb5 is unsubstituted cycloalkyl.
[0111] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 is aryl, wherein each aryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORb22, =0, -NRb23Rb24, -CN, -SF5, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rb28 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 Rb5 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 Rb28. In some embodiments, Rb28 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rb28 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, -NRb29Rb3°, -SFs, and -0Rb31. In some embodiments, Rb28 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, -NRb29Rb3°, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In some embodiments, at least one Rb5 is unsubstituted aryl.
[0112] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 is heteroaryl, wherein each heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rb28 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 Rb5 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 Rb28. In some embodiments, Rb28 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rb28 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, -NRb29Rb3°, -SFs, and -0Rb31. In some embodiments, Rb28 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRb29Rb3°, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In some embodiments, at least one Rb5 is unsubstituted heteroaryl. [0113] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 is heterocycloalkyl, wherein each heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, - ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rb28 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 Rb5 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 Rb28. In some embodiments, Rb28 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rb28 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, -NRb29Rb3°, -SFs, and -ORb31. In some embodiments, Rb28 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRb29Rb3°, -SFs, -OH, -O- (Ci-Ce)alkyl, and -0-(Ci-C6)haloalkyl. In some embodiments, at least one Rb5 is
unsubstituted heterocycloalkyl.
[0114] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rbl7, Rbl8, Rbl9, Rb20,
Figure imgf000060_0001
Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl. In certain embodiments, each R b!7
Tjbl8 Tjbl9 Tjb20 R b21 ¾b22 ¾rvb23, ¾ivb24, Rrvb25, ¾ivb26, ¾rvb27, Rivb54, R 55, Rivb56, Rrvb57, Rivb58, Rrvb59
IV , rv , Iv , rv , Iv , rvb , Rivb61,
Rb62, Rb63, and Rb64 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.
[0115] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rb20, Rb21, Rb22, Rb23, Rb24, Rb54, Rb55, Rb56, Rb57, Rb58, Rb59, Rb61, Rb62, Rb63, and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each Rb20, Rb21, Rb22, Rb23, Rb24, Rb25, Rb54, Rb55, Rb56, Rb57, Rb58, Rb59, Rb61, Rb62, Rb63, and Rb64 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocycloalkyl. In some embodiments, each Rbl7, Rbl8, Rb25, Rb26, and Rb27 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, each Rbl7, Rbl8,
Rb25, Rb26, and Rb27 is independently hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 3- to 10- membered heterocycloalkyl, 3- to lO-membered heteroaryl, or (C6-Cio)aryl. In some embodiments, each Rbl9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl. In certain embodiments, each Rbl9 is independently hydrogen, (Ci- C6)alkyl, (C3-C6)cycloalkyl, 3- to lO-membered heterocycloalkyl, (C6-Cio)aryl, 3- to 10- membered heteroaryl, or (C3-C6)alkynyl.
[0116] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, one or more Rb5 are independently selected from the group consisting of halo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro; -0-(C2-C4)alkynyl; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3-C6)cycloalkyl unsubstituted or substituted with one or more fluoro; and (Ci-Ce)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C6)cycloalkyl, aryl, halo, -OH, -O- (Ci-C4)alkyl, =0, -NRb26Rb27, and -CN.
[0117] In some embodiments, one or more Rb5 are independently selected from the group consisting of chloro; fluoro; bromo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro; -0-(C2-C4)alkynyl; and -CN. In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II- B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, n is 1 or 2, and each Rb5 is independently selected from the group consisting of chloro; fluoro; bromo; -0-(Ci- C6)alkyl unsubstituted or substituted with one or more fluoro; -0-(C2-C4)alkynyl; and -CN.
[0118] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb22, Rb23, Rb24, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31, wherein each aryl, heteroaryl, alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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.
[0119] In certain embodiments, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb22, Rb23, Rb24, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -ORb31, 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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently (C3-C6)cycloalkyl, 5- to 10- membered heterocycloalkyl, (C6-Cio)aryl, or 5- to lO-membered heteroaryl, and wherein each Rb66 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.
[0120] In certain embodiments, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31; 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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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.
[0121] In some embodiments, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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 10- membered heteroaryl, (Ci-Ce)alkyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, 5- to lO-membered heterocycloalkyl, -NRb29Rb3°, -SFs, and -ORb31; 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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently (C3-C6)cycloalkyl, 5- to 10- membered heterocycloalkyl, (C6-Cio)aryl, or 5- to lO-membered heteroaryl, and wherein each Rb66 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.
[0122] In some embodiments, each Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently hydrogen, alkyl, or haloalkyl. In certain embodiments, each Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl. [0123] In certain embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rb5 is:
Figure imgf000064_0001
wherein:
Rb33 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, -ORb36, -SFs, and - NRb37Rb38;
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, -ORb39, - NRb48Rb49, -NRb50C(O)Rb51, 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 Rb34 and Rb35 are 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, -ORb40, and -NRb41Rb42, 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 Rb34 and one Rb35 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 Rb36, Rb37, Rb38, Rb39, Rb40, Rb41, Rb42, Rb48, Rb49, Rb50, and Rb51 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
[0124] In some embodiments, each Rb36, Rb37, Rb38, Rb39, Rb40, Rb41, Rb42, Rb48, Rb49, Rb50, and Rb51 is independently hydrogen, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl. In certain
embodiments, each Rb36, Rb37, Rb38, Rb39, Rb40, Rb41, Rb42, Rb48, Rb49, Rb50, and Rb51 is independently hydrogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, or halobutyl.
[0125] In some embodiments, Rb33 is hydrogen. In other embodiments, Rb33 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, -ORb36, -SFs, and -NRb37Rb38. In still other embodiments, Rb33 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, -ORb36, -SFs, and -NRb37Rb38.
[0126] In certain embodiments, Rb33 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, -ORb39, -NRb48Rb49,
-NRb50C(O)Rb51, 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.
[0127] In some embodiments, Rb33 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, 3- to 6-membered heterocycloalkyl, (C6-Cio)aryl, and 3- to 6-membered heteroaryl; wherein the aryl, cycloalkyl, heterocycloalkyl, and heteroaryl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (Ci-C6)haloalkyl, (Ci-Ce)alkyl, -SFs, -OH, -0(Ci-C6)alkyl, =0, -NRb48Rb49, and -NRb50C(O)Rb51. In some embodiments, Rb33 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, -SFs, -NHC(0)-(Ci-C6)alkyl, and 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =0. In certain embodiments, Rb33 is (Ci-Ce)alkyl, wherein the alkyl is unsubstituted or substituted with one or more (C6-Cio)aryl or 3- to 6-membered heteroaryl.
[0128] In certain embodiments, Rb33 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rb33 is (Ci-Ce)alkyl substituted with 3- to 6-membered heteroaryl. In other embodiments, Rb33 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, Rb33 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.
[0129] In some embodiments, Rb33 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, Rb33 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. [0130] In some embodiments, Rb33 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. In other embodiments, Rb33 is 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci-C6)alkyl.
[0131] In some embodiments, Rb33 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, Rb33 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.
[0132] In still further embodiments, Rb33 is aryl, wherein the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (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, Rb33 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 one or more substituents independently selected from the group consisting of (Ci-C6)haloalkyl, -OH, -0(Ci-C6)alkyl, -SFs, -NHC(0)H, -NHC(0)-(Ci-C6)alkyl, =0, -NH2, and -NH(Ci-C6)alkyl.
[0133] In still further embodiments, Rb33 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.
[0134] In some embodiments, Rb33 is alkynyl. In certain embodiments, Rb33 is (C2- C6)alkynyl. [0135] In certain embodiments, Rb33 is:
Figure imgf000068_0001
[0136] In certain embodiments, Rb33 is:
Figure imgf000068_0002
[0137] In some embodiments, Rb34 and Rb35 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, Rb34 and Rb35 attached to the same carbon form an unsubstituted cyclopropyl or cyclobutyl. In some embodiments, Rb34 and Rb35 attached to the same carbon form a cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl are substituted with one or more halo.
[0138] In some embodiments, each Rb34 and Rb35 is hydrogen. In some embodiments, at least one Rb34 or Rb35 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, -ORb40, and -NRb41Rb42; 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. In some embodiments, at least one Rb34 or Rb35 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, aryl, 3- to 6-membered heteroaryl, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -ML·, -NH(Ci-C6)alkyl, -N((Ci- C6)alkyl)((Ci-C6)alkyl). In some embodiments, one Rb34 or one Rb35 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 Rb34 or one Rb35 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 Rb34 or one Rb35 is ethyl substituted with
difluorocyclopropyl .
[0139] In some embodiments, at least one Rb34 or Rb35 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 Rb34 or Rb35 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 Rb34 or Rb35 is alkyl substituted with 5- to 6-membered heteroaryl.
[0140] In some embodiments, q is 1. In still other embodiments, q is 2. In some
embodiments, q is 1, and one of Rb34 or Rb35 is hydrogen. In other embodiments, q is 2, and one Rb34 and two Rb35 are hydrogen. In other embodiments, q is 2, and two Rb34 and one Rb35 are hydrogen. In some embodiments, q is 2, and two Rb34 and three Rb35 are hydrogen. In some embodiments, q is 2, and three Rb34 and two Rb35 are hydrogen. [0141] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-ii), Formula (P-B), or Formula (II-B-ii), or a stereoisomer or
pharmaceutically acceptable salt thereof,
Figure imgf000070_0001
[0142] In some embodiments of the compound of Formula (I), Formula (II-A-i) or Formula (II-B-i), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000070_0002
[0143] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(O)-, -S(0)2-,
-S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-. In some embodiments, X is -S(0)2-, -C(O)-, or -C(Rbl3)2- In certain embodiments, X is -S(O)-, -S(0)2-, or -S(0)NRb53-. In other embodiments, X is -C(S)-, -C(O)-, or -C(Rbl3)2-
[0144] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(O)-.
[0145] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(0)2- [0146] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(0)NRb53-, wherein
Rb53 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, Rb53 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, Rb53 is hydrogen. In other embodiments, Rb53 is unsubstituted (Ci-Ce)alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In still other embodiments, Rb53 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, Rb53 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C3-C6)cycloalkyl, and =0.
[0147] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -C(S)-.
[0148] In some embodiments of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -C(O)-.
[0149] In some embodiments, of the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -C(Rbl3)2-, wherein each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl. In certain embodiments, each Rbl3 is independently hydrogen, halo, (Ci-Ce)alkyl, or (Ci-C6)haloalkyl. In some
embodiments, each Rbl3 is independently hydrogen, chloro, fluoro, methyl, ethyl, propyl, -CFhF, -CHF2, or -CF3. In some embodiments, each Rbl3 is H, and X is -CH2-.
[0150] In some embodiments of the compound of Formula Formula (I), (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B- ii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(0)2-, -C(O)-, or -CH2-.
[0151] In some embodiments, the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii) is:
Figure imgf000072_0001
Figure imgf000073_0001
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0152] In some embodiments, the compound of Formula (I) or Formula (II) is:
Figure imgf000074_0001
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0153] In some embodiments, the compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii) is:
Figure imgf000074_0002
Figure imgf000075_0001
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0154] In some embodiments, the compound of Formula (I) or Formula (II) is:
Figure imgf000075_0002
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0155] The compounds described herein, including compounds of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or their stereoisomers or pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, or other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( R )- or ( 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-pressure liquid chromatography (HPLC). While Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), and Formula (II-B-ii), and compounds of these formulae disclosed herein depict Rbl° and Rbu in a
trans orientation, as
Figure imgf000076_0001
, the stereoisomers of these formulae and compounds with
Rbl° and Rbu in a cis orientation, as
Figure imgf000076_0002
, are also provided herein. When the compounds described herein contain other 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.
[0156] “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, dodecyl sulfuric acid, ethane- l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, 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, l-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.
[0157] Unless otherwise stated, the compounds provided herein, including compounds of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II- B), Formula (II-B-i), or Formula (II-B-ii), or their stereoisomers or 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-l2 by a carbon-l3 (13C) or carbon-l4 (14C).
[0158] The compounds disclosed herein, such as a compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, may be prepared, for example, through the reaction routes depicted in General Scheme II- 1, General Scheme II-2, and General Scheme II-3.
General Scheme II- 1:
Figure imgf000077_0001
[0159] General Scheme II- 1 provides two routes to prepare a compound disclosed herein, such as a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or pharmaceutically acceptable salt thereof. In this scheme, compound 11-102 is combined with /er/-butyl but-3- yn-l-yl carbamate (compound 11-104), RhCl(PPh3)3, and solvent (such as dichloroethane, DCE), and that mixture stirred at room temperature to produce compound 11-106. This compound is then combined with meta-chloroperoxybenzoic acid (wCPBA) and solvent (such as dichloromethane, DCM), and that mixture stirred from 0 °C to room temperature to produce compound 11-108. This compound is 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 11-110. Compound 11-110 is combined with compound 11-112, l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate (HATU), triethylamine (Et3N), and solvent (such as DCM), and stirred at room temperature to produce compound 11-114. This compound is combined with TFA and a solvent (such as DCM) and stirred from 0 °C to room temperature to remove the BOC protecting group and produce compound 11-116. Following BOC removal, in route (A) the product 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 11-118, an example of a compound of Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-. Alternatively, in route (B) the product may be combined with triethylamine, solvent (such as DCM), HATU, and an RB- COOH reactant, and stirred at room temperature to produce compound 11-118, an example of a compound of Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
General Scheme II-2:
Figure imgf000079_0001
[0160] General Scheme II-2 provides another route to prepare a compound disclosed herein, such as a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A- ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or
pharmaceutically acceptable salt thereof. In this scheme, compound 11-202 is combined with 4-(trifluoromethyl)thiophenol (compound 11-204), Pd(OAc)2, and solvent (such as tetrahydrofuran, THF), and stirred at room temperature to produce compound 11-206. This compound is then combined with mCPBA and solvent (such as DCM) and stirred from 0 °C to room temperature to produce compound 11-208, which is an example of a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
General Scheme II-3:
Figure imgf000079_0002
[0161] General Scheme II-3 provides two routes to prepare a compound disclosed herein, such as a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or stereoisomer or pharmaceutically acceptable salt thereof. In this scheme, compound 11-302 is combined with /er/-butyl but-3- yn-l-yl carbamate (compound 11-304), Cp2Zr(H)Cl, and solvent (such as tetrahydrofuran, THF), and that mixture stirred from room temperature to 60 °C to produce compound 11-306. This compound is then combined with TFA and solvent (such as DCM) and stirred from 0 °C to room temperature to produce compound 11-308. Compound 11-308 is combined with compound 11-310, HATU, triethylamine, and solvent (such as DCM), and stirred at room temperature to produce compound 11-312. This compound is combined with TFA and a solvent (such as DCM) and stirred from 0 °C to room temperature to remove the BOC protecting group and produce compound 11-314. Following BOC removal, in route (A) compound 11-314 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 11-316, an example of a compound of Formula (II), Formula (P-A), Formula (II- A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
Alternatively, in route (B) compound 11-314 may be combined with triethylamine, solvent (such as DCM), HATU, and an RB-COOH reactant, and stirred at room temperature to produce compound 11-316, an example of a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
[0162] While General Schemes II- 1, II-2, and II-3 depict the synthesis of compounds of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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 wherein ring A is other than 5- or 6-membered heterocycloalkyl; wherein ring A is substituted; ring W is other than phenyl, or comprises substituents other than Cl; wherein Rb6, Rb7, Rb8, Rb9, Rbl°, or Rbu are other than hydrogen; or z is other than 1, may also be synthesized using routes analogous to General Schemes II- 1, II-2, and II-3. Furthermore, in some embodiments of any of these routes, one or more other solvents are used in one or more steps. In some embodiments, an amine other than triethylamine is used in one or more steps. In certain embodiments, the temperature may be adjusted. The reactants, solvents, and other compounds used to prepare a compound of Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, by following General Schemes II- 1, II-2, or II-3, or by another route, may be commercially available or may be prepared following organic chemical techniques.
[0163] Further provided herein is a pharmaceutical composition comprising a compound of Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient may include, for example, an adjuvant, carrier, 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
[0164] 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 (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II- B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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 (I), Formula (II), Formula (II-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II- B-ii), or a stereoisomer or 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. [0165] Also provided herein is the use of a compound of Formula (I), Formula (II),
Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
[0166] Further provided herein is a compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
[0167] 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.
[0168] In some embodiments, the disorder is neurofibromatosis type 1 (NF1), Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome. In certain 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.
[0169] 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 camcer 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 to a mutation or dysregulation of human K-Ras4b. In certain
embodiments, the cancer is related to aberrant K-Ras4b signaling pathway activity.
[0170] 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 (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer. 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 (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, is co-administered with one or more chemotherapeutic agents to a subject in need thereof.
[0171] 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 (I), Formula (II), Formula (P-A), Formula (II-A- i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof. In still another aspect, provided herein is a compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof. In a further aspect, provided herein is the use of a compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II- B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof. 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. In some embodiments, the K-Ras is aberrant K-Ras. In some embodiments, the K-Ras is mutant K-Ras. Reduction of the level of K-Ras may be evaluated, for example, by an immunoblot of a biological sample using one or more specific anti-K-Ras antibodies, or by mass spectrometry -based methods.
[0172] In some embodiments, administering a compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, to a subject may block one or more post-translational processing steps of a K-Ras precursor (such as K- Ras4a precursor or K-Ras4b precursor). This unprocessed precursor may then be degraded by the body, thus reducing the level of K-Ras protein. In some embodiments, the compound of Formula (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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 famesylation.
[0173] 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 (I), Formula (II), Formula (P-A), Formula (II-A- i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof. In still another aspect, provided herein is a compound of Formula (I), Formula (II), Formula (II- A), Formula (II-A-i), Formula (II-A-ii), Formula (P-B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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 (I), Formula (II), Formula (P-A), Formula (II-A-i), Formula (II-A-ii), Formula (II- B), Formula (II-B-i), or Formula (II-B-ii), or a stereoisomer or 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.
[0174] In some embodiments, both the activity of K-Ras and the level of K-Ras are reduced in a subject in need thereof.
[0175] “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.
[0176] 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, 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.
[0177] “ Co-administer" includes administering a compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or composition comprising any of these as described herein at the same time, just prior to, or just after the administration of one or more additional therapies, such as a chemotherapeutic agent. 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
[0178] Embodiment 1-1. A compound of Formula (I):
Figure imgf000086_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
z is 0, 1, or 2;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NRbl3Rbl4, -ORb15, -S02Rbl6, and -S02NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1; each Rb4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently
unsubstituted or substituted with one or more halo;
each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or Rb2 and Rb3 together form =0;
or Rb6 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb4, 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;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21;
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,
-ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63,
-S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rbl7 Rbl8 Rbl9 Rb20 Rb21 Rb22 Rb23 Rb24 Rb25 Rb26 Rb27 Rb54 Rb55 Rb56, RbS7 Rbs^ Rbs^ Rb6i^ Rb62^ Rb63^ and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb22, Rb23, Rb24, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31;
wherein each aryl, heteroaryl, alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl;
each Rbl2 is independently selected from the group consisting of halo, alkyl,
haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
[0179] Embodiment 1-2. The compound of Embodiment 1-1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, or cycloalkyl;
z is 0 or 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -CN, -OH, -NO2, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1;
each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
independently unsubstituted or substituted with one or more halo; and each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
or Rb2 and Rb3 together form =0;
or Rb6 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl; or Rbl° and Rbl, together with the atoms to which they are attached, form a heterocycloalkyl;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl;
or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl;
or two to four Rb4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21;
wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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 Rb28, wherein each Rb28 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 halo, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63,
-S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R^20 Rb24 Rk22 R^23 R^24 Rb54 Rb55 Rb56 Rb57 Rb58 Rb59 Rb64 j^b6 2
Rb63, and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; each Rbl7, Rbl8, Rb25, Rb26, and Rb27 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rbl9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7, Rbl8, Rbl9, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl of Rb65 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,
-NRb29Rb3°, -SFs, and -ORb31;
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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl;
each Rbl2 is independently selected from the group consisting of halo, alkyl,
haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
[0180] Embodiment 1-3. The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (II- A):
Figure imgf000092_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7; and
B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II).
[0181] Embodiment 1-4. The compound of any one of Embodiments 1-1 to 1-3, wherein the compound is of Formula (II-A-ii):
Figure imgf000092_0002
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
u is an integer from 0 to 5; and
B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
[0182] Embodiment 1-5. The compound of Embodiment 1-1 or 1-2, wherein the compound is of Formula (P-B):
Figure imgf000092_0003
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; and
B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II).
[0183] Embodiment 1-6. The compound of any one of Embodiments 1-1, 1-2, or 1-5, wherein the compound is of Formula (II-B-ii):
Figure imgf000093_0001
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; u is an integer from 0 to 5; and
B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
[0184] Embodiment 1-7. The compound of Embodiment 1-5 or 1-6, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CH2-.
[0185] Embodiment 1-8. The compound of Embodiment 1-1 or 1-2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
[0186] Embodiment 1-9. The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
[0187] Embodiment I- 10. The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
[0188] Embodiment 1-11. The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C9-Cio)bicyclic aryl.
[0189] Embodiment 1-12. The compound of any one of Embodiments 1-1 to 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C5-Cio)cycloalkyl.
[0190] Embodiment 1-13. The compound of any one of Embodiments 1-1 to 1-12, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one or more Rb5 are independently selected from the group consisting of halo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro; (C2-C4)alkynoxy; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3-C6)cycloalkyl unsubstituted or substituted with one or more fluoro; and (Ci-Ce)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C6)cycloalkyl, aryl, halo, -OH, -O- (Ci-C4)alkyl, =0,| -NRb26Rb27, and -CN.
[0191] Embodiment 1-14. The compound of any one of Embodiments 1-1 to 1-8, or 1-13, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
[0192] Embodiment 1-15. The compound of any one of Embodiments 1-1 to 1-4, 1-8, or I- 13, wherein the compound is of Formula (II-A-i):
Figure imgf000094_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and
X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
[0193] Embodiment 1-16. The compound of any one of Embodiments 1-1, 1-2, 1-5 to 1-8, or 1-13, wherein the compound is of Formula (II-B-i):
Figure imgf000095_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7;
Y is -C(Rb52)2-— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; u is an integer from 0 to 5; and
X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
[0194] Embodiment 1-17. The compound of any one of Embodiments 1-1 to 1-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rb5 is:
Figure imgf000095_0002
wherein: Rb33 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, -ORb36, -SFs, and -NRb37Rb38; 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, -ORb39, -NRb48Rb49,
-NRb50C(O)Rb51, 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 Rb34 and Rb35 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, -ORb40, and -NRb41Rb42; 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 Rb34 and one Rb35 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 Rb36, Rb37, Rb38, Rb39, Rb40, Rb41, Rb42, Rb48, Rb49, Rb50, and Rb51 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
[0195] Embodiment 1-18. The compound of Embodiment 1-17, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and Rb34 is hydrogen. [0196] Embodiment 1-19. The compound of any one of Embodiments 1-1 to 1-18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rb5 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 Rb28.
[0197] Embodiment 1-20. The compound of Embodiment 1-19, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rb28 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
[0198] Embodiment 1-21. The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl and one Rb4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
[0199] Embodiment 1-22. The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl and Rb8, together with the atoms to which they are attached, form a 3- to 6-membered
heterocycloalkyl.
[0200] Embodiment 1-23. The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl and Rb 10 , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
[0201] Embodiment 1-24. The compound of any one of Embodiments 1-1 to 1-23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
[0202] Embodiment 1-25. The compound of any one of Embodiments 1-1 to 1-23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
[0203] Embodiment 1-26. The compound of any one of Embodiments 1-1 to 1-23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CEb-
[0204] Embodiment 1-27. The compound of any one of Embodiments 1-1 to 1-14 or 1-17 to 1-26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2. [0205] Embodiment 1-28. The compound of any one of Embodiments 1-1, 1-2, 1-8 to 1-14, or 1-17 to 1-27, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
[0206] Embodiment 1-29. The compound of any one of Embodiments 1-3 to 1-7, 1-15, or 1-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.
[0207] Embodiment 1-30. The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl° and Rbu are independently selected from the group consisting of hydrogen, fluoro, -CN, unsubstituted methyl, and methyl substituted with one to three fluoro.
[0208] Embodiment 1-31. The compound of any one of Embodiments 1-1 to 1-30, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rbl2 is chloro.
[0209] Embodiment 1-32. The compound of any one of Embodiments 1-1 to 1-3, 1-5, 1-7 to 1-14, or 1-17 to 1-30, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
Figure imgf000098_0001
[0210] Embodiment 1-33. The compound of any one of Embodiments 1-4, 1-6, 1-15, or I-
16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
Figure imgf000098_0002
Figure imgf000098_0003
[0211] Embodiment 1-34. The compound of any one of Embodiments 1-1 to 1-32, wherein z is 0 or 1.
[0212] Embodiment 1-35. The compound of Embodiment 1-1 or 1-34, wherein the compound is:
Figure imgf000099_0001
Figure imgf000100_0001
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0213] Embodiment 1-36. The compound of Embodiment 1-1, wherein the compound is:
Figure imgf000100_0002
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0214] Embodiment 1-37. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0215] Embodiment 1-38. 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 therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0216] Embodiment 1-39. The method of Embodiment 1-38, wherein the K-Ras protein is human K-Ras4b.
[0217] Embodiment 1-40. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
[0218] Embodiment 1-41. The method of Embodiment 1-40, wherein the disorder is cancer.
[0219] Embodiment 1-42. The method of Embodiment 1-41, 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.
[0220] Embodiment 1-43. The method of Embodiment 1-40, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
[0221] Embodiment 1-44. The method of any one of Embodiments 1-40 to 1-43, wherein the disorder is associated with a mutation of K-Ras.
[0222] Embodiment 1-45. ETse of a compound of any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof.
[0223] Embodiment 1-46. The use of Embodiment 1-45, wherein the K-Ras protein is human K-Ras4b. [0224] Embodiment 1-47. Use of a compound of any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
[0225] Embodiment 1-48. The use of Embodiment 1-47, wherein the disorder is cancer.
[0226] Embodiment 1-49. The use of Embodiment 1-48, 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.
[0227] Embodiment 1-50. The use of Embodiment 1-47, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
[0228] Embodiment 1-51. The use of any one of Embodiments 1-47 to 1-50, wherein the disorder is associated with a mutation of K-Ras.
[0229] Embodiment 1-52. A compound according to any one of Embodiment 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
[0230] Embodiment 1-53. The compound for use of Embodiment 1-52, wherein the K-Ras protein is human K-Ras4b.
[0231] Embodiment 1-54. A compound according to any one of Embodiments 1-1 to 1-36, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
[0232] Embodiment 1-55. The compound for use of Embodiment 1-54, wherein the disorder is cancer.
[0233] Embodiment 1-56. The compound for use of Embodiment 1-55, 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.
[0234] Embodiment 1-57. The compound for use of Embodiment 1-54, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
[0235] Embodiment 1-58. The compound for use of any one of Embodiments 1-54 to 1-57, wherein the disorder is associated with a mutation of K-Ras.
EXAMPLES
[0236] The following Examples are merely illustrative and are not meant to limit any aspects of the present disclosure in any way.
Example II- 1: Synthesis of tert-butyl (3-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate and tert-butyl (E)-(4-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate
Figure imgf000103_0001
[0237] A mixture of 4-chlorobenzenethiol, /er/-butyl but-3-yn-l-yl carbamate,
dichloroethane (DCE), and RhCl(PPh3)3 (5 mol%) was stirred at room temperature for 18 hours to produce a mixture of tert-butyl (3-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate and tert-butyl (E)-(4-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate. These two compounds were inseparable. Example II-2: Synthesis of tert-butyl (3-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamate and tert-butyl (E)-(4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)carbamate
Figure imgf000104_0001
[0238] A mixture of tert-butyl (3-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate and tert- butyl (E)-(4-((4-chlorophenyl)thio)but-3-en-l-yl)carbamate was combined with meta- chloroperoxybenzoic acid (wCPBA; 77%) in dichloromethane (DCM) and stirred from 0 °C to room temperature for 18 hours to produce a mixture of tert-butyl (3 -((4- chlorophenyl)sulfonyl)but-3-en-l-yl)carbamate and tert-butyl (E)-(4-((4- chlorophenyl)sulfonyl)but-3-en-l-yl)carbamate. These compounds were separated.
Example II-3: Synthesis of (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-l-amine
Figure imgf000104_0002
[0239] The compound tert-butyl (E)-(4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)carbamate was combined with trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 hour to produce (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-l -amine.
Example II-4: Synthesis of tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamoyl)piperidine-l-carboxylate
Figure imgf000104_0003
[0240] The compound (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-l -amine was combined with (ri)-l-(ter/-Butoxycarbonyl)piperidine-3 -carboxylic acid, l-[Bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (E1ATEG), triethylamine, and dichloromethane, and the mixture stirred at room temperature for 18 h to produce tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)carbamoyl)piperidine-l-carboxylate.
Example II-5: Two Syntheses of (S,E)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4- chlorophenyl)sulfonyl)but-3-en-l-yl)piperidine-3-carboxamide
Figure imgf000105_0001
[0241] The compound (S,E)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4- chlorophenyl)sulfonyl)but-3-en-l-yl)piperidine-3 -carboxamide was synthesized from tert- butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)carbamoyl)piperidine-l- carboxylate using two different methods.
[0242] Route 1: In the first route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en- l-yl)carbamoyl)piperidine-l-carboxylate was combined with trifluoroacetic acid and dichloromethane, and that mixture stirred for 18 h from 0 °C to room temperature to remove the tert-butyloxycarbonyl (BOC) protecting group. The deprotected product was combined with 5-chloro-2-methoxybenzoic acid, AHTEG, triethylamine, and dichloromethane, and the mixture stirred at room temperature for 18 h to produce (S,E)-l-(5-chloro-2- methoxybenzoyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)piperidine-3 -carboxamide.
[0243] Route 2: In the second route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3- en-l-yl)carbamoyl)piperidine-l-carboxylate is deprotected as described for Route 1, then the deprotected product combined with 5-chloro-2-methoxybenzoyl chloride, triethylamine, and dichloromethane, and the mixture stirred at room temperature for 4 h to produce (S,E)-l-(5- chloro-2-methoxybenzoyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)piperidine-3- carboxamide. Example II-6: Synthesis of (S)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4- (trifluoromethyl)phenyl)sulfonyl)but-3-en-l-yl)piperidine-3-carboxamide
Figure imgf000106_0001
[0244] The compound (S)-N-(but-3 -yn- 1 -yl)- 1 -(5-chloro-2-methoxybenzoyl)piperidine-3 - carboxamide was combined with 4-(trifluoromethyl)thiophenol, Pd(OAc)2 (5 mol%), and tetrahydrofuran, and mixture stirred at room temperature for 18 h to produce (S)-l-(5-chloro- 2-methoxybenzoyl)-N-(4-((4-(trifluoromethyl)phenyl)thio)but-3-en-l-yl)piperidine-3- carboxamide. This product was then combined with wCPBA (77%) and dichloromethane, and the mixture stirred from 0 °C to room temperature for 18 h to produce (S)-l-(5-chloro-2- methoxybenzoyl)-N-(4-((4-(trifluoromethyl)phenyl)sulfonyl)but-3-en-l-yl)piperidine-3- carboxamide.
Example II-7: Synthesis of tert-butyl (E)-(4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamate
Figure imgf000106_0002
[0245] The compound 4-chlorobenzenesulfonyl chloride was combined with /er/-butyl but-3- yn-l-yl carbamate, Cp2Zr(H)Cl (1.2 eqv.), and tetrahydrofuran, and the mixture stirred from room temperature to 60 °C for 18 h to produce tert-butyl (E)-(4-((4- chlorophenyl)sulfonyl)but-3-en-l-yl)carbamate.
Example II-8: Synthesis of (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-l-amine
Figure imgf000106_0003
[0246] The compound (S)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4-
(trifluoromethyl)phenyl)sulfonyl)but-3-en-l-yl)piperidine-3 -carboxamide was combined with trifluoroacetic acid and dichloromethane and the mixture stirred from 0 °C to room temperature for one hour to produce (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-l-amine.
Example II-9: Synthesis of tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamoyl)pyrrolidine-l-carboxylate
Figure imgf000107_0001
[0247] The compound (E)-4-((4-chlorophenyl)sulfonyl)but-3-en-l -amine was combined with (S)-l-(fer/-butoxycarbonyl)pyrrolidine-3 -carboxylic acid, E1ATEG, triethylamine, and dichloromethane, and the mixture stirred at room temperature for 18 h to produce tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)carbamoyl)pyrrolidine-l-carboxylate.
Example 11-10: Two Syntheses of (S,E)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4- chlorophenyl)sulfonyl)but-3-en-l-yl)pyrrolidine-3-carboxamide
Figure imgf000107_0002
[0248] The compound (S,E)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4- chlorophenyl)sulfonyl)but-3-en-l-yl)pyrrolidine-3 -carboxamide was synthesized from tert- butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)carbamoyl)pyrrolidine-l- carboxylate using two different methods. [0249] Route 1: In the first route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)carbamoyl)pyrrolidine-l-carboxylate was combined with trifluoroacetic acid and dichloromethane, and that mixture stirred for 18 h from 0 °C to room temperature to remove the tert-butyloxycarbonyl (BOC) protecting group. The deprotected product was combined with 5-chloro-2-methoxybenzoic acid, HATU, triethylamine, and dichloromethane, and this mixture stirred at room temperature for 18 h to produce (S,E)-l-(5-chloro-2- methoxybenzoyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-l-yl)pyrrolidine-3-carboxamide.
[0250] Route 2: In the second route, tert-butyl (S,E)-3-((4-((4-chlorophenyl)sulfonyl)but-3- en-l-yl)carbamoyl)pyrrolidine-l-carboxylate was deprotected as described in Route 1. The deprotected product was then combined with 5-chloro-2-methoxybenzoyl chloride, dichloromethane, and triethylamine, and the mixture stirred at room temperature for 4 h to produce (S,E)-l-(5-chloro-2-methoxybenzoyl)-N-(4-((4-chlorophenyl)sulfonyl)but-3-en-l- yl)pyrrolidine-3-carboxamide.
[0251] Compounds synthesized using methods similar to those described in the above Examples are provided in Table II- 1.
Table II-l. Synthesized Compounds
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0002
Table II-2. Characterization of Synthesized Compounds
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
[0252] NMR spectroscopy: 'H NMR spectra were recorded at 300 MHz on a Varian Mercury NMR spectrometer at ambient temperature. Samples were prepared in deuterated chloroform (CDCb), or deuterated dimethylsulphoxide (DMSO-r/^), or other appropriate deuterated solvent. Chemical shifts are reported in parts per million (ppm) relative to deuterated solvent, or a TMS internal standard. Multiplicities are reported as follows: s = singlet; d = doublet, t = triplet; q = quartet; m = multiplet; br = broad.
[0253] LCMS analysis: For certain compounds, LCMS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separations module and Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software. The HPLC column used was an Agilent ZORBAX Eclipse XDB-C18 4.6x150, 3.5u Rapid Resol column with a mobile phase of water (0.1 % formic acid) / MeCN (0.1% formic acid) and a gradient of 5-95% MeCN over 5 minutes at a flow rate of 1 mL/min.
[0254] For other compounds, LCMS analysis was conducted on a Thermo Scientific- Finnigan, performed on a Phenomenex Gemini 5mM Cl 8 110 A, 50 x 3.0 mm column with a flow rate of lmL/minute. Detection by UV and mass-ion was undertaken. Two different analytical methods were used for this work, the details of which are presented below.
[0255] 6mins-0.5mL-min-Pos-only method (6 min): Performed on a Phenomenex Gemini 5mM C18 1 IqA, 50 x 3.0 mm column with a flow rate of lmL/minute using 0.1% v/v Formic acid in water [Eluent A]; MeCN [Eluent B]; Flow rate lmL/min;
Figure imgf000114_0001
[0256] 10mins-0.5mL-min-Pos-only method (10 min): 0.1% v/v formic acid in water
[Eluent A]; 0.1% v/v formic acid in MeCN [Eluent B]; Flow rate 0.8mL/min; injection volume 2 pL and 1.5 min equilibration time between samples.
Figure imgf000114_0002
Example 11-11: Covalent modification analysis using Matrix Assisted Laser
Desorption/Ionization - Time of Flight Mass Spectrometry (MALDI-TOF MS)
[0257] Compounds of the synthesized library were evaluated for covalent modification of KRAS4b 1-188 protein using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), to confirm covalent labeling at Cl 85.
[0258] Reaction: 20 mM of KRAS4b (1-188) protein (Protein Expression Laboratory, FNLCR/Leidos Biomed.) in 20 mM HEPES buffer containing 150 mM NaCl, 1 mM MgCh, 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. The contents of the wells were mixed by aspiration, then the plate is sealed by adhesive cover, centrifuged at 2000 g for 1 minute, and incubated in the dark at room temperature for 24 h.
[0259] 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.
[0260] 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.
[0261] 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 is set to x9 (1734 V), sample rate to 1 GS/s, smart beam parameter set: 3_medium is used, and the laser frequency is 66.7 Hz. Spectra were automatically collected using a custom AutoXecute method. Laser power is auto-adjusted using fuzzy control. The peak selection range was set to be between 20500 and 23000 Da. Peak evaluation uses half width parameter set to be smaller than 30 Da. Fuzzy control uses Proteins/Oligonucleotides protocol with minimum half width 1/6 times above threshold. Up to 1500 shots were collected in 500 shot steps. Dynamic termination was implemented to finish data collection when peak intensity is reaching value of 1200 [a.u.].
[0262] 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.
[0263] Results of the analysis of selected compounds is listed in Table II-3 below.
Compound 11-0096 (pyrrolidine) had greater reactivity than 11-0017 (piperidine). The decreased reactivity of the other pyrrolidine compounds as evaluated by MALDI may be a result of precipitation of compound in aqueous MALDI matrix due to lower aqueous solubility. Their hydrophobicity may lead to greater cell permeability, and therefore better activity in cells.
Table II-3. Covalent modification of KRAS4b 1-188 protein by pyrrolidine compounds.
Figure imgf000116_0002
Figure imgf000116_0001
[0264] Results of the analysis of selected piperidine-containing compounds is listed in Table II-4 below.
Table II-4. Covalent binding of selected piperidine-containing compounds.
Figure imgf000116_0003
Example 11-12: Compound labeling of GDP compared with GppNHp forms of KRAS4b protein
[0265] The labeling of active (GppNHp) and inactive (GDP) forms of KRAS4b cells by selected compounds was evaluated using MALDI-TOF mas spectrometry. Nucleotide exchange of GDP KRAS4b was used to prepare GppNHp-loaded KRAS4b 1-188 (a non- hydrolysable analogue of GTP KRAS4b).
[0266] GppNHp nucleotide exchange: One hundred fifty to 300 mM solution of GDP loaded protein in KRAS buffer (20 mM HEPES, 150 mM NaCl, 1 mM MgCk, 0.05 mM TCEP, pH 7.3) was prepared. Fifteen-hundred molar excess of 1 M ammonium sulfate in KRAS buffer was added and mixed gently by inverting tube. A 250 mM solution of GppNHp was prepared (150 molar excess of GppNHp to protein, on ice). Ten percent of prepared GppNHp solution was added to protein, then suspension of alkaline phosphatase from calf intestine on agarose (Sigma- Aldrich, P0726) was added, to final concentration of 2 units of enzyme per each mg of protein. Reaction mixture was incubated at room temperature, rotating end-over for 1 h 30 min. Alkaline phosphatase on agarose beads was removed by filtering solution to a new vial using Millex-GP syringe filter. Remaining solution of GppNHp was added and incubated for additional 45 min. At the end of the exchange protein was filtered again, placed on ice and purified on NGC medium-pressure chromatography system (Bio-Rad). Five in-lane connected desalting columns (5 c GE Healthcare HiTrap Desalting columns 5 ml, 17-1408-01) were used with isocratic elution of KRAS buffer at 4 ml/min. The protein elution was monitored at 280 nm. The concentration of final protein was evaluated by NanoDrop 2000 spectrophotometer (Thermo Fisher) using molar attenuation coefficient e = 19685 l-moE'-cm- 1. The quality of the protein was confirmed by MALDI- TOF MS, and the exchange rate assessed by HPLC-based assay exceeded 98%.
[0267] A heat map comparing the covalent labeling of the two different proteins by selected compounds is provided in FIG. 1. This figure suggests that nucleotide loading (active GppNHp, compared to GDP-loaded KRAS4b) does not influence levels of KRAS4b 1-188 covalent labeling. This might suggest noncovalent docking to a different pocket of the protein than the Switch II pocket, which is available only in GDP -KRAS.
Example 11-13: Cellular uptake and stability in cells
[0268] The cellular uptake and stability of compound 11-0017 in cells was evaluated in MiaPaCa-2 pancreas carcinoma cells grown on 10 cm dishes. A compound was added to the complete growth medium at 10 mM final concentration. After incubation for time points indicated on the graph (FIG. 2), cells were rinsed three times with ice-cold PBS, then placed on ice, and excess of PBS was removed with aspiration. Cells were scraped into 300 mΐ of ice-cold methanol, spun down at 20,000g x 15 min, and the resulting supernatant filtered to HPCL vial, then subjected to analysis by Finnigan LTQ mass spectrometer connected to Agilent microHPLC system using Phenomenex Kinetex Cl 8 column. A graph of detected compound concentration over time is provided in FIG. 2. Compound 11-0017 was still detectable in cells after 72h of incubation. Half-life of compound 11-0017 with 10 mM GSH was also measured, and equaled 250 min.
[0269] MiaPaCa-2 cells were plated at 2xl05 per dish onto 10 cm dishes, and allowed to attach overnight. Cells were treated for 72 h with DMSO or 10 mM to 50 pM compound II- 0017 (compound added once). Compound 11-0017 appeared to be active at 20 pM
concentration, causing growth arrest without signs of acute toxicity. Images of the cells are shown in FIG. 3.
Example 11-14: Cell proliferation assays
[0270] Compounds of the synthesized library were also evaluated using cell-based screens with RASless mouse embryonic fibroblasts (MEFs). Cell viability in the presence of synthesized compounds was measured using CellTiter-Glo® (Promega). The proliferation assay was performed using mouse embryonic fibroblasts (MEF) expressing a single isoform of RAS (KRAS4b Q61R, KRAS4b G12V as a model system, and Myr-KRAS4b
G12D/C185S, and HRAS WT as controls).
[0271] 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 pl), using the Multidrop Combi Reagent Dispenser (Thermo). They were then incubated overnight at 37 °C in a humidified atmosphere of 5% CO2 prior to compound 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%.
[0272] 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).
[0273] 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
[0274] Dose-response curves were generated using Prism 7 software (GraphPad).
[0275] FIG. 4 is a heat map of the ICso values for selected compounds in KRAS G12 mutants and control MEF lines. Cells expressing oncogenic mutants KRAS4b G12V and KRAS4b Q61R show higher sensitivity to these compounds, compared with cells driven by HRAS WT or Myr-KRAS4b G12D/C185S (negative control).
Example 11-15: Western Blot Evaluation of Compound 11-0017
[0276] Compound 11-0017 was evaluated in a Western blot analysis of KRAS total protein level. Two cancer cell lines were used, HupT4 (pancreas cancer line bearing KRAS G12V mutant) and H1792 (lung adenocarcinoma bearing G12C mutant). KRAS protein level was evaluated by Western blot after 72 h treatment with the compound, using three different anti- RAS antibodies (as indicated in FIG. 5A). MEK total protein level was used as a loading control. 11-0017 caused dose-dependent decreased level of KRAS protein in both cell lines. Inhibition of cell proliferation was also observed, as shown on the example of H1792 lung adenocarcinoma cell line treated with increasing concentrations of compound 11-0017 for 72 h (FIG. 5B). Example 11-16: Evaluation of Compound 11-0144 via Cycloaddition
Figure imgf000120_0001
[0277] An alkyne analogue of compound 11-0096, compound 11-0144, was evaluated in a cycloaddition reaction with Alexa Fluor 647-azide, to investigate target engagement in cells. HEK293 cells expressing 3xFLAG KRAS4b G12V in doxycycline-inducible lentiviral vector were used. KRAS expression in these cells was induced with 200 ng/ml doxycycline for 24h, followed by addition of the compound for another 24h. Cells were fractionated into cytosolic and membrane fractions, and the cytosolic fraction was used for purification of KRAS4b G12V using Flag Ml agarose (Sigma- Aldrich) following manufacturer protocol. Protein was eluted from Flag Ml agarose using 0.1 M glycine buffer pH 2.7, and neutralized immediately with 1 : 10 1M Tris pH 8.0. Whole cell lysates (WCL) of DMSO-treated cells and 11-0144- treated cells were also collected.
[0278] Alexa Fluor 647-azide was used to detect compound 11-0144 covalently attached to KRAS4b G12D purified from cells on Flag Ml agarose, via the ligation or“click”
conjugation between the alkyne moiety and an azide-containing fluorescent dye, according to the reaction scheme below.
[0279] FIG. 6 depicts gel images of the Alexa Fluor 647 signal (negative from whole cells lysates that were not subjected to the click conjugation reaction) and positive for pull-down (Pd) of Flag-KRAS4b from HEK293 expressing KRAS4b G12V treated with 11-0144, after click-reaction has been performed. LMW = low molecular weight standards.
Example 11-17: Immunoblot analysis
[0280] Certain compounds of the synthesized library are evaluated for effect on localization of KRAS in cell membranes.
[0281] Cells are rinsed thrice with ice-cold PBS and then are lysed on ice with ice-cold TNE buffer supplemented with Halt protease and phosphatase inhibitors (Thermo Scientific). This is then centrifuged at 15,000 for 15 minutes to collect whole-cell lysates. Protein concentration is measured with the BCA protein assay (Pierce). Thirty micrograms of total protein per sample is loaded into 4%-l2% NuPAGE Bis-Tris gradient gels (Life
Technologies) and separated by SDS-PAGE. Proteins are transferred to polyvinylidene difluoride (PVDF) membranes. The following antibodies are used for immunoblotting: mouse monoclonal anti-KRAS (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 -ART (Cell Signaling Technology 2920). Vinculin (rabbit anti-vinculin, Cell Signaling Technology 4650) is used as a loading control. Primary antibodies are detected with fluorescence-conjugated (LI-COR) secondary antibodies.
[0282] For cell fractionation experiments, cells are seeded at 2xl05 onto lO-cm Petri dishes and allowed to grow for 24 h. Compounds are added to the medium to a final concentration 10 - 30 mM for 72h. Cells are rinsed three times with ice-cold PBS, then digitonin [300 mΐ of 190 mg/ml in lysis buffer (PBS containing 75 mM KC1, 250 mM sucrose and Halt protease and phosphatase inhibitors (Thermo)] is added for 10 min on ice. Cells are then scraped gently and centrifuged 10 min at 12,000 at 4 °C. The supernatant (cytosolic fraction) is removed, and the remaining pellet (membrane fraction) is resuspended in 100 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 are 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.
Example 11-18: Tumor Xenograft
[0283] 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.
[0284] 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 11-19: Synthesis of (E)-tert-butyl 4-(2-((4-chlorophenyl) sulfonyl)vinyl) piperidine-l-carboxylate
Figure imgf000122_0001
[0285] The compound tert-butyl 4-ethynylpiperidine-l-carboxylate was combinated with bis(cyclopentadienyl)zirconium chloride hydride at room temperature under argon. A solution of 4-chlorobenzene- l-sulfonyl chloride in THF was added and the solution was stirred at 60 °C. The reaction mixture was cooled to room temperature and ~50 ml water was added. The mixture was extracted with EtOAc, washed, filtered and the solvent was evaporated to produce (E)-tert-butyl 4-(2-((4-chlorophenyl) sulfonyl)vinyl) piperidine-l- carboxylate.
Example 11-20: Synthesis of (E)-4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidine
Figure imgf000122_0002
[0286] The compound (E)-tert-butyl 4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidine-l- carboxylate was treated with TFA at room temperature for 30 minutes to afford the (E)-4-(2- ((4-chlorophenyl)sulfonyl)vinyl)piperidine.
Example 11-21: Synthesis of (S,E)-(4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidin-l- yl)(pyrrolidin-3-yl)methanone
Figure imgf000123_0001
[0287] The compound (E)-4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidine was combined with !TATU, (S)-l-(tert-butoxycarbonyl)pyrrolidine-3 -carboxylic acid, DCM, and triethylameine and the resulting solution was stirred at room temperature for 18 hours. The resulting compound was treated with TFA and was stirred at room temperature for 30 minutes to produce (S,E)-(4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidin-l-yl)(pyrrolidin-3- yl)methanone.
Example 11-22: Synthesis of (S,E)-(l-(5-chloro-2-methoxybenzoyl)pyrrolidin-3-yl)(4-(2- ((4-chlorophenyl)sulfonyl)vinyl)piperidin-l-yl)methanone (1-0000756)
Figure imgf000123_0002
[0288] The compound (S,E)-(4-(2-((4-chlorophenyl)sulfonyl)vinyl)piperidin-l- yl)(pyrrolidin-3-yl)methanone was added to a solution of 5-chloro-2-methoxybenzoyl chloridewith triethylamine and the reaction mixture stirred at room temperature overnight to produce the (S,E)-(l-(5-chloro-2-methoxybenzoyl)pyrrolidin-3-yl)(4-(2-((4- chlorophenyl)sulfonyl)vinyl)piperidin- 1 -yl)methanone. Example 11-23: Synthesis of (E)-3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidine
Figure imgf000124_0001
[0289] The compound tert-butyl 3-ethynylazetidine-l-carboxylate was combinated with bis(cyclopentadienyl)zirconium chloride hydride at room temperature under argon. A solution of 4-chlorobenzene- l-sulfonyl chloride in THF was added and the solution was stirred at 60°C. The reaction mixture was cooled to room temperature and ~50 ml water was added. The mixture was extracted with EtOAc, washed, filtered and the solvent was evaporated. The resulting compound was treated with trifluoroacetic acid to produce (E)-3- (2-((4-chlorophenyl)sulfonyl)vinyl)azetidine.
Example 11-24: Synthesis of (S,E)-(3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidin-l- yl)(pyrrolidin-3-yl)methanone
Figure imgf000124_0002
[0290] The compound (S)-l-(tert-butoxycarbonyl)pyrrolidine-3 -carboxylic acid was added to 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium
hexafluorophosphate(V), and the solution was stirred for 30 minutes. A solution of (E)-3-(2- ((4-chlorophenyl)sulfonyl)vinyl) azetidine and triethylamine was added and the solution stirred at room temperature for 3 hours to produce (S,E)-tert-butyl 3-(3-(2-((4- chlorophenyl)sulfonyl)vinyl)azetidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate which was treated with TFA to produce (S,E)-(3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidin-l- yl)(pyrrolidin-3-yl)methanone. Example 11-25: Synthesis of (S,E)-(l-(5-chloro-2-methoxybenzoyl)pyrrolidin-3-yl)(3-(2- ((4-chlorophenyl)sulfonyl) vinyl)azetidin-l-yl)methanone (1-0000757)
Figure imgf000125_0001
[0291] The compound (S,E)-(3-(2-((4-chlorophenyl)sulfonyl)vinyl)azetidin-l- yl)(pyrrolidin-3-yl)methanone was treated with triethylamine and 5-chloro-2- methoxybenzoyl chloride at room temperature and the resulting solution was stirred at toom temperature overnight to produce (S,E)-(l-(5-chloro-2-methoxybenzoyl)pyrrolidin-3-yl)(3- (2-((4-chlorophenyl)sulfonyl) vinyl)azetidin-l-yl)methanone.

Claims

CLAIMS What is claimed is:
1. A compound of F ormul a (I) :
Figure imgf000126_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; z is 0, 1, or 2;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -CN, -N02,-NRbl3Rbl4, -ORb15, -S02Rbl6, and -S02NH2, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo, and wherein when one of Rb6 and Rb7 is alkyl, z is 1; each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, aryl, -N02, -CN, -S02NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo; each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or Rb2 and Rb3 together form =0; or Rb6 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is unsubstituted or substituted with one or more halo;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or two to four Rb4, 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;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NCte, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21;
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, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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,
-ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63, -S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rbl7 R^18 Rbl9 Rb20 Rb21 Rb22 Rb23 Rb24 Rb25 Rb26 Rb27 Rb54 Rb55 Rb56, Rbs? Rb58^ Rb59^ Rb6i^ Rb62^ Rb63^ and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7,
RM8, RbW Rb22^ Rb23^ Rb24^ Rb25^ Rb26^ Rb27^ and Rb28^ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rb65 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, -NRb29Rb3°, -SFs, and -ORb31;
wherein each aryl, heteroaryl, alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl;
each Rbl2 is independently selected from the group consisting of halo, alkyl,
haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
t is an integer from 0 to 6.
2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
W is aryl or heteroaryl;
X is -S(O)-, -S(0)2-, -S(0)NRb53-, -C(S)-, -C(O)-, or -C(Rbl3)2-;
each Rbl3 is independently hydrogen, halo, alkyl, or haloalkyl;
Rb53 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;
Rbl is hydrogen, alkyl, or cycloalkyl;
z is 0 or 1;
Rb2, Rb3, Rb6, Rb7, Rb8, Rb9, Rbl°, and Rbu are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, -CN, -OH, -NO2, -NH2, and -SO2NH2, wherein when one of Rb6 and Rb7 is alkyl, z is 1;
each Rb4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRbl3Rb14, -ORb15, =0, -SRb60, and -S02Rbl6;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
independently unsubstituted or substituted with one or more halo; and each Rbl3, Rbl4, Rbl5, Rbl6, and Rb60 is independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
or Rb2 and Rb3 together form =0;
or Rb6 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rbl° and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rb8 and Rbl, together with the atoms to which they are attached, form a
heterocycloalkyl; or two to four Rb2, Rb3, Rb6, and Rb7, together with the atoms to which they are attached, form a heterocycloalkyl or heteroaryl;
or Rbl and one Rb4, together with the atoms to which they are attached, form a
heterocycloalkyl;
or two to four Rb4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
each Rb5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRb54Rb55, -NRbl7Rb18, -ORb19, -S02Rb2°, =0, and -SRb21;
wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORb22, =0, -NRb23Rb24, -CN, -SFs, -S02NRb56Rb57, -SRb58, -S02Rb59, and Rb28, wherein each Rb28 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 Rb28, wherein each Rb28 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 halo, -ORb25, =0, -NRb26Rb27, -CN, -SFs, -S02NRb61Rb62, -SRb63, - S02Rb64, and Rb65, wherein each Rb65 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R^20 Rb24 Rk22 R^23 R^24 Rb54 Rb55 Rb56 Rb57 Rb58 Rb59 Rb64 j^b6 2
Rb63, and Rb64 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
each Rbl7, Rbl8, Rb25, Rb26, and Rb27 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rbl9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rbl7,
Rbl8, Rbl9, Rb25, Rb26, Rb27, and Rb28, and each cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl of Rb65 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,
-NRb29Rb3°, -SFs, and -ORb31; 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, -NRb43Rb44, -NRb45C(0)Rb46, -ORb47, and Rb66, wherein each Rb66 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rb66 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 Rb29, Rb30, Rb31, Rb43, Rb44, Rb45, Rb46, and Rb47 is independently
hydrogen, alkyl, or haloalkyl; each Rbl2 is independently selected from the group consisting of halo, alkyl,
haloalkyl, and -ORb32, wherein Rb32 is hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 1 1 ; and t is an integer from 0 to 6.
3. The compound of claim 1 or 2, wherein the compound is of Formula (P-A):
Figure imgf000131_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; and
B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II).
4. The compound of any one of claims 1 to 3, wherein the compound is of Formula (II- A-ii):
Figure imgf000132_0001
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and
B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
5. The compound of claim 1 or 2, wherein the compound is of Formula (P-B):
Figure imgf000132_0002
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4; r is 0, 1, or 2; and
B, W, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, n, and t are as defined for Formula (II).
6. The compound of any one of claims 1, 2, or 5, wherein the compound is of Formula (II-B-ii):
Figure imgf000133_0001
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4;
r is 0, 1, or 2;
u is an integer from 0 to 5; and
B, X, Rb4, Rb5, Rbl°, Rbu, Rbl2, and n are as defined for Formula (II).
7. The compound of claim 5 or 6, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CH2-.
8. The compound of claim 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
9. The compound of any one of claims 1 to 8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered heterocycloalkyl or 5- or 6- membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
10. The compound of any one of claims 1 to 8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
11. The compound of any one of claims 1 to 8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C9-Cio)bicyclic aryl.
12. The compound of any one of claims 1 to 8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C5-Cio)cycloalkyl.
13. The compound of any one of claims 1 to 12, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one or more Rb5 are independently selected from the group consisting of halo; -0-(Ci-C6)alkyl unsubstituted or substituted with one or more fluoro; (C2- C4)alkynoxy; phenyl; heteroaryl; heterocycloalkyl; -SO2NH2; -NO2; -CN; (C3-C6)cycloalkyl unsubstituted or substituted with one or more fluoro; and (Ci-Ce)alkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C3-C6)cycloalkyl, aryl, halo, -OH, -0-(Ci-C4)alkyl, =0, -NRb26Rb27, and -CN.
14. The compound of any one of claims 1 to 8, or 13, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
15. The compound of any one of claims 1 to 4, 8, or 13, wherein the compound is of Formula (II-A-i):
Figure imgf000134_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 7; u is an integer from 0 to 5; and
X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
16. The compound of any one of claims 1, 2, 5 to 8, or 13, wherein the compound is of Formula (II-B-i):
Figure imgf000135_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(Rb52)2-,— S(0)r— , -0-, or -N(Rb52)-, wherein each Rb52 is independently hydrogen or Rb4;
r is 0, 1, or 2;
u is an integer from 0 to 5; and
X, Rb4, Rb5, Rbl°, Rbu, and Rbl2 are as defined for Formula (II).
17. The compound of any one of claims 1 to 16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rb5 is:
Figure imgf000135_0002
wherein:
Rb33 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, -ORb36, -SFs, and -NRb37Rb38; 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, -ORb39,
-NRb48Rb49, -NRb50C(O)Rb51, 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 Rb34 and Rb35 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, -ORb40, and -NRb41Rb42; 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 Rb34 and one Rb35 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 Rb36, Rb37, Rb38, Rb39, Rb40, Rb41, Rb42, Rb48, Rb49, Rb50, and Rb51 is independently hydrogen, alkyl, or haloalkyl; and q is 1 or 2.
18. The compound of claim 17, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and Rb34 is hydrogen.
19. The compound of any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rb5 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 Rb28.
20. The compound of claim 19, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rb28 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
21. The compound of any one of claims 1, 2, 8 to 14, or 17 to 20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl and one Rb4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
22. The compound of any one of claims 1, 2, 8 to 14, or 17 to 20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl and Rb8, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
23. The compound of any one of claims 1, 2, 8 to 14, or 17 to 20, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl and Rbl° , together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl.
24. The compound of any one of claims 1 to 23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
25. The compound of any one of claims 1 to 23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
26. The compound of any one of claims 1 to 23, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CFh-
27. The compound of any one of claims 1 to 14 or 17 to 26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
28. The compound of any one of claims 1, 2, 8 to 14, or 17 to 27, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
29. The compound of any one of claims 3 to 7, 15, or 16, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein p is 0.
30. The compound of any one of claims 1 to 29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rbl° and Rbu are independently selected from the group consisting of hydrogen, fluoro, -CN, unsubstituted methyl, and methyl substituted with one to three fluoro.
31. The compound of any one of claims 1 to 30, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rbl2 is chloro.
32. The compound of any one of claims 1 to 3, 5, 7 to 14, or 17 to 30, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
Figure imgf000138_0001
33. The compound of any one of claims 4, 6, 15, or 16, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
Figure imgf000138_0002
34. The compound of any one of claims 1 to 33, wherein z is 0 or 1.
35. The compound of claim 1 or 34, wherein the compound is:
Figure imgf000138_0003
Figure imgf000139_0001
Figure imgf000140_0001
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
36. The compound of claim 1, wherein the compound is:
Figure imgf000140_0002
or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
38. 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 therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
39. The method of claim 38, wherein the K-Ras protein is human K-Ras4b.
40. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
41. The method of claim 40, wherein the disorder is cancer.
42. The method of claim 41, 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.
43. The method of claim 40, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
44. The method of any one of claims 40 to 43, wherein the disorder is associated with a mutation of K-Ras.
45. Use of a compound of any one of claims 1 to 36, or a stereoisomer or
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof.
46. The use of claim 45, wherein the K-Ras protein is human K-Ras4b.
47. Use of a compound of any one of claims 1 to 36, or a stereoisomer or
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
48. The use of claim 47, wherein the disorder is cancer.
49. The use of claim 48, 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.
50. The use of claim 47, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
51. The use of any one of claims 47 to 50, wherein the disorder is associated with a mutation of K-Ras.
52. A compound according to any one of claims 1 to 36, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
53. The compound for use of claim 52, wherein the K-Ras protein is human K-Ras4b.
54. A compound according to any one of claims 1 to 36, or a stereoisomer or
pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
55. The compound for use of claim 54, wherein the disorder is cancer.
56. The compound for use of claim 55, 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.
57. The compound for use of claim 54, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
58. The compound for use of any one of claims 54 to 57, wherein the disorder is associated with a mutation of K-Ras.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021257736A1 (en) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
WO2023205701A1 (en) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Macrocyclic heterocycles and uses thereof
EP4389751A1 (en) 2021-09-03 2024-06-26 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6916817B1 (en) * 1999-06-04 2005-07-12 Astrazeneca Ab Inhibitors of metalloproteinases
US8324239B2 (en) * 2010-04-21 2012-12-04 Novartis Ag Furopyridine compounds and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6916817B1 (en) * 1999-06-04 2005-07-12 Astrazeneca Ab Inhibitors of metalloproteinases
US8324239B2 (en) * 2010-04-21 2012-12-04 Novartis Ag Furopyridine compounds and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem compound 10 September 2014 (2014-09-10), "1-Methyl-4-[4-(2-methylsulfonylethenyl)piperidin-1-yl]-2-oxoquinoline-3-carbonitrile", XP055645768, retrieved from NCBI Database accession no. 77141576 *
DATABASE PubChem compound 26 October 2006 (2006-10-26), "4-[(E)-2-(Benzenesulfonyl)ethenyl]-1-(4-methylphenyl)sulfonylpiperidine", XP055645765, retrieved from NCBI Database accession no. 11750091 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021257736A1 (en) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
EP4389751A1 (en) 2021-09-03 2024-06-26 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof
WO2023205701A1 (en) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Macrocyclic heterocycles and uses thereof

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