WO2019204442A1 - K-ras modulators with a cyanoacrylamide moiety - Google Patents

K-ras modulators with a cyanoacrylamide moiety Download PDF

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Publication number
WO2019204442A1
WO2019204442A1 PCT/US2019/027876 US2019027876W WO2019204442A1 WO 2019204442 A1 WO2019204442 A1 WO 2019204442A1 US 2019027876 W US2019027876 W US 2019027876W WO 2019204442 A1 WO2019204442 A1 WO 2019204442A1
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iii
alkyl
cycloalkyl
heterocycloalkyl
formula
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PCT/US2019/027876
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French (fr)
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Anna E. Maciag
David Turner
Matthew Alexander James Duncton
Adam R. Renslo
Eddy Low
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Theras, Inc.
Leidos Biomedical Research, Inc.
The Regents Of The University Of California
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Publication of WO2019204442A1 publication Critical patent/WO2019204442A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

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

Abstract

Provided herein are compounds comprising a cyanoacrylamide 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 CYANO ACRYLAMIDE MOIETY
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U S. Provisional Application No. 62/659,599, 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 KRAS that produces a K-Ras protein, and more specifically to inhibitors with a cyanoacryl amide moiety.
BACKGROUND
[0004] KRAS is one of the most frequently mutated oncogenes implicated in human cancer. The KiM-S' oncogene encodes the K-Ras protein, which is part of the RAS/MAPK signaling pathway. K-Ras is a GTPase that acts as a molecular switch, flipping between an active GTP-bound form and an inactive GDP -bound form. The K-Ras protein plays a crucial role in tissue signaling, and is involved in cell proliferation, cell differentiation, and apoptosis. Activating mutations in KRAS are common in many different human cancers. Thus, what is needed in the art are effective inhibitors of K-Ras, and effective inhibitors of the post- translational processing of KRAS that produces a mature, full-processed K-Ras protein.
BRIEF SUMMARY
[0005] In one aspect, provided herein is a compound of Formula (III):
Figure imgf000003_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2-, -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2-;
each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
Rc50 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;
Rcl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NRc8Rc9, -ORcl°, and -SC Rc11, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCh, -CN, -SO2NH2, - NRC8RC9, _0Rc I°, =0, -SRc51, and -S02Rc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc2 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc3 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rc2 and Rc3, 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 Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRC52Rc53, -NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16;
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, -ORc17, =0, -NRC18Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56,
-S02Rc57, and Rc23, wherein each Rc23 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, ORc20, =0, NRC21Rc22, CN, SFs, S02NRC58Rc59, SRc60,
-S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000005_0001
Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl\ Rcl4, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rc62 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, -NRC24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NFh, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -CN, -SFs, -NO2, =0, -ORc27, and -NRc28Rc29; wherein each alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, -O- alkyl, -OH, -O-haloalkyl, =0, -CN, -NH2, and -SFs; and each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13; n is an integer from 0 to 11; and
v is an integer from 0 to 11.
[0006] In some variations of the compound of Formula (III), or a steroisomer or pharmaceutically acceptable salt thereof, Z is aryl or heteroaryl. In some variations, A is 5- or 6-membered heterocycloalkyl.
[0007] In some variations, the compound of Formula (III) is a compound of Formula (III-
A):
Figure imgf000006_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; and B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
[0008] In other variations, the compound of Formula (III) is a compound of Formula (III- A-ii):
Figure imgf000006_0002
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; d is an integer from 0 to 5; and B, X, Rc4, Rc5, Rc6, and n are as defined for Formula (III).
[0009] In some variations, the compound of Formula (III) is a compound of Formula (III- B):
Figure imgf000007_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; Y is -C(RC49)2- -S(0)r-, -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4; r is 0, 1, or 2; and B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
[0010] In certain variations, the compound of Formula (III) is a compound of Formula (III- B-ii):
Figure imgf000007_0002
ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; Y is -C(RC49)2-, -S(0)r-, -O-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4 ; r is 0, 1, or 2; d is an integer from 0 to 5; and B, X, Rc4, Rc5, Rc6, and n are as defined for Formula (IP).
[0011] In some of the variations described herein, Y is -CH2-.
[0012] In some variations, B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three heteroatoms independently selected from the group consisting of O, N, and S. In other variations, B is a 9- or 10-membered bicyclic heteroaryl comprising one to three heteroatoms independently selected from the group consisting of O, N, and S. In still other variations, B is a (C9- Cio)bicyclic aryl. In certain variations, B is a (C5-Cio)cycloalkyl. [0013] In some variations, Z is a 5-membered heteroaryl. In certain variations, Z is a 9- membered heteroaryl. In other variations, Z is a 6-membered heteroaryl. In still other variations, Z is alkyl or cycloalkyl.
[0014] In some variations, the compound of Formula (III) is a compound of Formula (III- A-i):
Figure imgf000008_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; d is an integer from 0 to 5; and X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0015] In other variations, the compound of Formula (III) is a compound of Formula (III- B-i):
Figure imgf000008_0002
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; Y is -C(RC49)2-, -S(0)— , -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4; r is 0, 1, or 2; d is an integer from 0 to 5; and X, Rc4, Rc5, and Rc6 are as defined for Formula (III). [0016] In still other variations, the compound of Formula (III) is a compound of Formula (III-A-iii):
Figure imgf000009_0001
-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; d is an integer from 0 to 5; and X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0017] In certain variations, the compound of Formula (III) is a compound of Formula (III- B-iii):
Figure imgf000009_0002
iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 7; Y is -C(RC49)2-, -S(0)— , -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4; r is 0, 1, or 2; d is an integer from 0 to 5; and X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0018] In some variations of the compound of Formula (III), Formula (III-A), Formula (III- A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III- B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 is:
Figure imgf000010_0001
wherein:
Rc30 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, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORc33, -SFs, and -NRc34Rc35;
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, -ORc36,
-NRC45Rc46, -NRC47C(0)Rc48, 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 Rc31 and Rc32 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, -ORc37, and
-NRC38Rc39;
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 Rc31 and one Rc32 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 Rc33, Rc34, Rc35, Rc36, Rc37, Rc38, Rc39, Rc45, Rc46, Rc47, and Rc48 is independently hydrogen, alkyl, or haloalkyl;
and q is 1 or 2.
[0019] In some variations, X is -S(0)2- In other variations, X is -C(O)-. In still further variations, X is -CH2- In some variations, n is 1 or 2. In certain variations, m is 0. In some variations, p is 0.
[0020] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some variations, the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
stereoisomer or pharmaceutically acceptable salt thereof.
[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 (III), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some variations, the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer
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 (III), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some variations, the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
[0023] In yet a further aspect, provided herein is the use of a compound of Formula (III), 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 (III) is a compound of Formula (III- A), Formula (III-A- i), Formula (III-A-ii), Formula (III-A-iii), Formula (PI-B), Formula (III-B-i), Formula (III-B- ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
[0024] In another aspect, provided herein is the use of a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof. In some variations, the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B- iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
[0025] In still a further aspect, provided herein is a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof. In some variations, the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B- iii), or a stereoisomer or pharmaceutically acceptable salt thereof.
[0026] In yet another aspect, provided herein is a compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof. In some variations, the compound of Formula (III) is a compound of Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
stereoisomer or pharmaceutically acceptable salt thereof.
[0027] In certain variations of any 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.
DETAILED DESCRIPTION
[0028] 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.
[0029] Provided herein is a compound, such as a compound of Formula (III), Formula (III- A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III- B-i), Formula (III-B-ii), or Formula (PI-B-iii), or a stereoisomer or pharmaceutically acceptable salt of any of the foregoing, as described below. In some embodiments, this compound or stereoisomer or pharmaceutically acceptable salt thereof may inhibit K-Ras, or may inhibit the post-translational processing of KRAS that produces a K-Ras protein, such as K-Ras4b. For example, in some embodiments, this compound may block the farnesylation of the newly synthesized K-Ras, preventing its C-terminal processing. In other embodiments, this compound or 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 or stereoisomer or pharmaceutically acceptable salt thereof as described herein may be administered in a therapeutically effective amount to a subject in need thereof in a method of treating a disorder in a subject. The disorder may be, for example, a disorder associated with a mutation of KRAS. The disorder may be, for example, a disorder associated with a mutation in a K-Ras protein. In some embodiments, the compound or stereoisomer or pharmaceutically acceptable salt thereof inhibits K-Ras, or decreases the level of K-Ras, or inhibits the post-translational processing of KRAS to produce a mature, fully-processed K-Ras protein, such as K-Ras4b. The compounds, stereoisomers, and pharmaceutically acceptable salts thereof; compositions comprising said compounds, stereoisomers, and pharmaceutically acceptable salts thereof; and methods of using said compounds stereoisomers, and pharmaceutically acceptable salts thereof and compositions of the present disclosure are described in greater detail below I. Compounds of Formula (III)
[0030] Provided herein is a compound of Formula (III):
Figure imgf000014_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2- -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2-;
each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
Rc50 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;
Rcl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRc8Rc9, -ORcl°, and -S02Rc11, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -S02Rc11; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -NIL·, -NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SO3H, -SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC(0)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; and
each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl; or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc2 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc3 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rc2 and Rc3, 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 Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRC52Rc53, -NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16; 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, -ORc17, =0, -NRcl8Rc19, -CN, -SFS, -S02NRC54Rc55, -SRc56,
-S02Rc57, and Rc23, wherein each Rc23 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,
— ORc20, =0, -NRC21Rc22, -CN, -SFs, -S02NRc58Rc59, -SRc60,
-S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000016_0001
Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, RcS0, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rc62 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, -NRC24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, CN, SFs, =0, NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 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 Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -SO2NH2, -CN, -SF5, -NO2,
=0, -ORc27, and -NRc28Rc29;
wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, -O-alkyl, -OH, -O-haloalkyl, =0, -CN, -NH2, -SFs,
-NH(alkyl), -COOH, -C(0)0-alkyl, -CONH2, -NO2, -SH, -S-alkyl, -SOsH, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)-alkyl, -NHC(0)0- alkyl ,-NHC(0)0H, -NHOH, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
and each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13;
n is an integer from 0 to 11; and
v is an integer from 0 to 11.
[0031] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rc4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -S02Rc11; 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. -CFs, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2,
CHI2, OH, COOH, SH, SO3H, SO4H, SO2NH2, NHNΉ2, ONH2,
-NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHC(0)-alkyl, -NHC(0)0-alkyl, -NHOH, -OCCb, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br,
OCH2F, OCH2I, OCHCh, OCHBn, OCHF2, OCHI2, CONH2, -NO2, NH(alkyl), -C(0)0-alkyl, -O-alkyl, alkyl (such as (Ci-Cs)alkyl, (Ci-C6)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).
[0032] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S02NH2, -CN, -SF5, -N02, =0, -ORc27, and -NRc28Rc29; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -NHz,
CCI3, -CBn, -CFs, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCk, -CHBr2, -CHF2, CHI2, -OH, -COOH, -SH, -SO3H, -S04H, -S02NH2, -NHNH2, -ONH2,
-NHC(0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H, -NHC(0)0H, -NHC(0)-alkyl, -NHC(0)0-alkyl, -NHOH, -OCCb, -OCBn, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBn, -OCHF2, -OCHI2, -CONH2, -N02, -NH(alkyl), -C(0)0-alkyl, -O-alkyl, alkyl (such as (Ci-Cs)alkyl, (Ci-C6)alkyl, or (Ci-C4)alkyl), cycloalkyl (such as (C3-C8)cycloalkyl, (C3-C6)cycloalkyl, or (C5-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).
[0033] In some embodiments of the compound of Formula (III):
Figure imgf000018_0001
or a stereoisomer or pharmaceutically acceptable salt thereof:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2-, -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2-;
each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
Rc50 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;
Rcl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NRc8Rc9, -ORcl°, and -S02Rc11, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCh, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -SCkRc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc2 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Rc3 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rc2 and Rc3, 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 Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NC , -CN,
-S02NRC52Rc53, -NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16;
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, -ORc17, =0, -NRcl8Rc19, -CN, -SFS, -S02NRC54Rc55, -SRc56,
-S02Rc57, and Rc23, wherein each Rc23 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, -ORc20, =0, -NRc21Rc22, -CN, -SFs, -S02NRc58Rc59, -SRc60,
-S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rcl2, Rcl3, Rcl4, Rcl5, Rcl6, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, Rc52, Rc53, Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rc62 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,
-NRc24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NH2, -SF5, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -CN, -SFs, -NO2, =0, -ORc27, and -NRc28Rc29; wherein each alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, -O- alkyl, -OH, -O-haloalkyl, =0, -CN, -NH2, and -SFs; and each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13;
n is an integer from 0 to 11, and
v is an integer from 0 to 11. [0034] In certain embodiments of the compound of Formula (III):
Figure imgf000022_0001
or a stereoisomer or pharmaceutically acceptable salt thereof:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Z is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2-, -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2-;
each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
Rc50 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;
Rcl is hydrogen, alkyl, or cycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, SO2NH2, -NRc8Rc9, -ORcl°, and -S02RcU, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -SC>2Rc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is independently unsubstituted or substituted with one or more halo; each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
or Rc2 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rc2 and Rc3, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl;
each Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRC52Rc53, -NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16,
wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORc17, =0, -NRcl8Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56, -S02Rc57, and Rc23, wherein each Rc23 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 Rc23, wherein each Rc23 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, -ORc20, =0, -NRC21Rc22, -CN, -SFs, -S02NRc58Rc59, -SRc60,
-S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 63.ch Rcl5 Rcl6 Rcl7 J^cl8 cl9 j^c52 j^c53 j^c54 j^c55 j^c56 j^c57 J^c58 j^c59
Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
each Rcl2, Rcl3, Rc20, Rc21, and Rc22 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, or aryl;
each Rcl4 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of Rc62 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,
-NRC24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NFb, SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, haloalkyl,
-ORc27, and -NRc28Rc29, wherein each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and v is an integer from 0 to 11.
[0035] In certain embodiments of the compound of Formula (III), 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.
[0036] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000025_0001
integer from 0 to 12. In other
embodiments,
Figure imgf000025_0002
integer from 0 to 12.
[0037] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, Rcl is hydrogen, alkyl, or cycloalkyl. In certain embodiments, Rcl is hydrogen, (C i- jalkyl, or (C3-C6)cycloalkyl. In some embodiments, Rcl is hydrogen. In other embodiments, Rcl is (Ci-C6)alkyl. For example, in some embodiments, Rcl is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, Rcl is (C3-C6)cycloalkyl. For example, in some embodiments, Rcl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0038] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt hereof, Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NRC8Rc9, -ORc1°, and -S02Rc11, wherein each alkyl, cycloalkyl, and
heterocycloalkyl is independently unsubstituted or substituted with one or more halo. In certain embodiments, Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered haloheterocycloalkyl, -NO2, -CN, -SO2NH2, -NRC8Rc9, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, and -S02Rc11. In some embodiments, Rc2 and Rc3 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and -OH. In some embodiments, Rc2 and Rc3 are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, hexyl, halomethyl, haloethyl, halopropyl, halobutyl, halopentyl, halohexyl, -OH, methoxy, ethoxy, propoxy, and butoxy. In some embodiments, one of Rc2 and Rc3 is hydrogen. In some embodiments, Rc2 and Rc3 are both hydrogen.
[0039] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, Rc2 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo. In some
embodiments, Rc2 and one Rc4, together with the atoms to which they are attached, form a (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. In certain embodiments, the cycloalkyl is unsubstituted. In other embodiments, Rc2 and one Rc4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In certain embodiments, the heterocycloalkyl is unsubstituted. In certain embodiments, Rc2 and one Rc4, together with the atoms to which they are attached, form a C3- cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. The cycloalkyl or heterocycloalkyl formed by Rc2 and Rc4 may be fused to ring A. For example, in some embodiments,
Figure imgf000026_0001
In some embodiments, Rc3 is hydrogen. [0040] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, Rc3 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo. In some
embodiments, Rc3 and one Rc4, together with the atoms to which they are attached, form a (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the cycloalkyl is unsubstituted. In other embodiments, Rc3 and one Rc4, together with the atoms to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the heterocycloalkyl is unsubstituted. In certain embodiments, Rc3 and one Rc4, together with the atoms to which they are attached, form a C3- cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo. The cycloalkyl or heterocycloalkyl formed by Rc3 and Rc4 may be fused to ring A. For example, in some embodiments,
Figure imgf000027_0001
some embodiments, Rc2 is hydrogen.
[0041] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, Rcl and one Rc4, together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the heterocycloalkyl is unsubstituted. For example, in certain embodiments, Rcl and one Rc4, 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. For example, in some embodiments,
Figure imgf000028_0001
[0042] In some embodiments, Rc2 or Rc3 is hydrogen. In other embodiments, both of Rc2 and Rc3 are hydrogen. In some embodiments, m is 0. Thus, in some embodiments,
Figure imgf000028_0002
[0043] It should be understood that in some embodiments, wherein Rc2 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein Rc3 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; or wherein Rcl and one Rc4, together with the atoms to which they are attached, form a heterocycloalkyl; there may exist one or more other Rc4
independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRc8Rc9, -ORcl°, =0, -SRc51, and -S02Rcl1, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently unsubstituted or substituted with one or more halo. For example, in some embodiments of Formula (III), m is 3; Rc2 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining two Rc4 are independently halo or alkyl. In some embodiments of Formula (III), m is 4; Rc3 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl; and the remaining three Rc4 are independently -OH, halo, alkyl, or haloalkyl.
[0044] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, Rc2 and Rc3, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or
heterocycloalkyl is unsubstituted or substituted with one or more halo. For example, in some embodiments, Rc2 and Rc3, together with the atom to which they are attached, form a (C3- C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo.
In some embodiments the cycloalkyl is unsubstituted. In other embodiments, Rc2 and Rc3, together with the atom to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments the heterocycloalkyl is unsubstituted.
[0045] In some embodiments of the compound of Formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof, Rcl and Rc2, together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more halo. In some embodiments, the heterocycloalkyl is
unsubstituted. For example, in some embodiments, Rcl and Rc2, together with the atom to which they are attached, form a 3- to 6-membered heterocycloalkyl, wherein the
heterocycloalkyl is unsubstituted or substituted with one or more halo.
[0046] "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-C5o)alkyl), 1 to 20 carbon atoms ((Ci-C2o)alkyl), 1 to 12 carbon atoms ((Ci-Ci2)alkyl), 1 to 8 carbon atoms ((Ci-C8)alkyl), 1 to 6 carbon atoms ((Ci-C6)alkyl), or 1 to 4 carbon atoms ((Ci-C4)alkyl). 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.
[0047] “Haloalkyl”, as used herein, refers to an alkyl group substituted with one or more halo, which may be selected independently. Thus, haloalkyl includes alkyl substituted with one or more halo independently selected from the group consisting of fluoro, chloro, iodo, and bromo. Haloalkyl may include, for example, -CH2F, -CHF2, -CF3, -CH2CI, -CHCI2, -CCh, -CH2CHFCI, -CHFCH3, -CH2Br, and -CH2CHFCH2CH2Br.
[0048] “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.
[0049] “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-C5o)alkynyl), 2 to 20 carbon atoms ((C2-C2o)alkynyl), 2 to 12 carbon atoms ((C2-Ci2)alkynyl), 2 to 10 carbon atoms ((C2-Cio)alkynyl), 2 to 8 carbon atoms ((C2-C8)alkynyl), 2 to 6 carbon atoms ((C2-C6)alkynyl), or 2 to 4 carbon atoms ((C2- C4)alkynyl). Alkynyl may have one, two, three, four, five, or more carbon-carbon triple bonds, as valency permits. When an alkynyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
[0050] “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)cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro- li/-indene, decahydronaphthalene, cubane, bicyclo[3. l.0]hexane, and bicyclof 1.1.1 jpentane.
[0051] “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.
[0052] "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; 1,2,3,4-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 ofN, O, and S (e.g., chromane; thiochromane; 2,3-dihydrobenzofuran; indoline). In some embodiments, aryl as used herein has from 6 to 14 carbon atoms ((C6- Ci4)aryl), or 6 to 10 carbon atoms ((C6-Cio)aryl). Where the aryl includes fused rings, the aryl may connect to one or more substituents or moieties of the formulae described herein through any atom for which valency permits.
[0053] "Fleteroaryl", as used herein, refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S. The heteroaryl group may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g., be a 5-membered, 6-membered, 7- membered, 8-membered, 9-membered, 10-membered, 11-membered, or l2-membered heteroaryl). 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.
[0054] “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.
[0055] “Halo” or“halogen” includes bromo, chloro, fluoro, and iodo.
[0056] 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.
[0057] 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 Ci, C2, Cs, C4, Cs, Ce, Ci-6, Ci-s, CM, C M, CI-2, CM, CM, CM, CM, CB-6, CS-S, C3-4, CM, CM, and C5-6 alkyl.
[0058] In some embodiments, the compound of Formula (III) is a compound of Formula (III-A):
Figure imgf000033_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7; and
B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
[0059] In some embodiments of the compound of Formula (III-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.
[0060] In certain embodiments, the compound of Formula (III) is a compound of Formula (III-B):
Figure imgf000033_0002
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7; Y is -C(RC49)2- -S(0)r- -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2; and
B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
[0061] In some embodiments of the compound of Formula (III-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.
[0062] In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is aryl or heteroaryl. In some embodiments, Z is (C6-Cio)aryl. In certain embodiments, Z is 5- to 8- membered heteroaryl. In certain embodiments, Z is 5- to 7-membered heteroaryl. In some embodiments, Z is 5-, 6-, or 7-membered heteroaryl. In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is 5- to 10-membered heteroaryl, wherein the heteroaryl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, Z is 5- or 6-membered heteroaryl, wherein the heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, Z is 9- or 10-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, Z is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl.
[0063] In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is pyridazinyl, pyrazolyl, pyrrolyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, naphthyridinyl, or pyrrolyl. In certain embodiments of the compound of Formula (IP), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is:
Figure imgf000035_0001
[0064] In other embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is aryl. For example, in some embodiments, Z is (C6-Cio)aryl, such as C6-aryl, (C7-Cio)bicyclic aryl, (Cs- Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl. In certain embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is phenyl or naphthyl. In some embodiments, Z is an aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring, for example (C7- Cio)bicyclic aryl, (C8-Cio)bicyclic aryl, or (C9-Cio)bicyclic aryl comprising a phenyl ring fused to a cycloalkyl or heterocycloalkyl ring. In certain embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is:
Figure imgf000036_0001
[0065] In other embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is alkyl. In certain embodiments, Z is (Ci-C6)alkyl. For example, in some embodiments, Z is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, Z is propyl.
[0066] In other embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is cycloalkyl. For example, in some embodiments, Z is (C3-Cio)cycloalkyl. In certain embodiments, Z is (C5-Cio)cycloalkyl. In other embodiments, Z is (C5-C7)cycloalkyl. In still other embodiments, Z is (C8-Cio)cycloalkyl. In some embodiments, Z is C3-cycloalkyl, C4- cycloalkyl, Cs-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or Cio- cycloalkyl. In some embodiments, Z is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl. In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, or tricyclooctyl. In certain embodiments of the compound of Formula (IP), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is:
Figure imgf000036_0002
[0067] In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is heterocycloalkyl. In some embodiments, Z is 5- to 10-membered heteroaryl, or 5- to 10- membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl comprises one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, Z is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, Z is 9- or 10-membered bicyclic heteroaryl comprising one to three ring heteroatoms
independently selected from the group consisting of O, N, and S.
[0068] In certain embodiments of a compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is a 5- membered heteroaryl. In some embodiments, Z is pyrazolyl, thiophenyl, furanyl, or oxazolyl. In other embodiments, Z is a 9-membered heteroaryl. In certain embodiments, Z is benzothiophenyl or indolyl. In still other embodiments, Z is a 6-membered heteroaryl. In some embodiments, Z is alkyl or cycloalkyl.
[0069] In some embodiments of the compound of Formula (III) or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen. In other embodiments, Z is alkyl. In further embodiments, Z is cycloalkyl. In some embodiments, Z is aryl. In certain embodiments, Z is 6- to 10-membered heteroaryl. In still other embodiments, Z is 5-membered heteroaryl comprising two or more annular N atoms. In some embodiments, Z is or 5-membered heteroaryl comprising at least one annular O or S atom.
[0070] It should be understood that in embodiments described herein, Z may be
unsubstituted or substituted with 1 to 11 Rc6 as described in Formula (III), Formula (III-A), and Formula (IP-B), as valency allows. For example, in some embodiments, Z is
Figure imgf000037_0001
, as
described above,
Figure imgf000037_0002
, wherein v is an integer from 0 to 5. In some
Figure imgf000038_0001
embodiments, Z is N"NH as described above, and (R° ^ is N'NH ; wherein v is an
integer from 0 to 3. For example, in some embodiments,
Figure imgf000038_0002
[0071] In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, v is an integer from 0 to 11. In certain embodiments, v is an integer from 0 to 10, or from 0 to 8, or from 0 to 6, or from 1 to 11, or from 1 to 9, or from 1 to 7, or from 2 to 11, or from 2 to 9, or from 2 to 7, or from 2 to 5, or from 3 to 11, or from 3 to 9, or from 3 to 7, or from 3 to 5. In some embodiments, v is an integer from 0 to 5. In other embodiments, v is an integer from 0 to 4. In still further embodiments, v is an integer from 0 to 3. In certain embodiments, v is 0, 1, or 2. In other embodiments, v is an integer from 1 to 6, or from 2 to 6, or from 3 to 6, or from 3 to 5, or from 2 to 4. In certain embodiments, v is 0. In other embodiments, v is 1 In some embodiments, v is 2. In still other embodiments, v is 3. In still further embodiments, v is 4. In some embodiments, v is 5. In certain embodiments, v is 6.
[0072] In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is hydrogen and v is 0.
[0073] In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof, Z is phenyl, and v is an integer from 0 to 5. In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000038_0003
, wherein d is an integer from 0 to 5. [0074] In certain embodiments, the compound of Formula (III) is a compound of Formula (III-A-ii):
Figure imgf000039_0001
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
B, X, Rc4, Rc5, Rc6, and n are as defined for Formula (III).
[0075] In some embodiments of the compound of Formula (III-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, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
[0076] In some embodiments, the compound of Formula (III) is a compound of Formula (III-B-ii):
Figure imgf000039_0002
ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7; Y is -C(RC49)2- -S(0)r- -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4 ;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
B, X, Rc4, Rc5, Rc6, and n are as defined for Formula (III).
[0077] In some embodiments of the compound of Formula (III-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, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
[0078] In certain embodiments of the compound of Formula (III-B) or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, Y is -C(Rc49)2-, wherein each Rc49 is independently hydrogen or Rc4. In certain embodiments, Y is -CH2-. In other embodiments, Y is -CHRc4-. In some embodiments, Y is -C(Rc4)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(Rc49)-, wherein Rc49 is hydrogen or Rc4. For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NRc4-.
[0079] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is 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 10- membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
[0080] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is 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 10- 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 (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or tropanyl. In certain embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is:
Figure imgf000041_0001
[0081] In other embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is heteroaryl. For example, in some embodiments, B is 5- to 10- membered heteroaryl comprising one to five ring heteroatoms independently selected from the group consisting of O, N, and S. In other embodiments, B is 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, B is 9- or lO-membered heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 9- or 10-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S. In some embodiments, B is a 5,5-ring fused heteroaryl, 6,6-ring fused heteroaryl, or 5,6-ring fused heteroaryl. In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (IP-B), or Formula (III-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 (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is:
Figure imgf000042_0001
[0082] In other embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is 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 (IP), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is phenyl 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 (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is:
Figure imgf000043_0001
[0083] In still further embodiments of the compound of Formula (IP), Formula (III-A), Formula (III-A-ii), Formula (IP-B), or Formula (III-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 (Ce- Cio)cycloalkyl. In some embodiments, B is C3-cycloalkyl, C4-cycloalkyl, Cs-cycloalkyl, C6- cycloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C9-cycloalkyl, or Cio-cycloalkyl. In some embodiments, B is a 5,5-ring fused cycloalkyl, 6,6-ring fused cycloalkyl, or 5,6-ring fused cycloalkyl. In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (IP-B), or Formula (III-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 (III), Formula (III-A), Formula (III-A-ii), Formula (IP-B), or Formula (III-B-ii), or a stereoisomer or
pharmaceutically acceptable salt thereof, B is:
Figure imgf000044_0001
[0084] It should be understood that for embodiments described herein, B may be unsubstituted or substituted with one to eleven Rc5 as described in Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), as valency allows. For
Figure imgf000044_0002
( B)-(Rc5)
example, in some embodiments, B is as described above, and IS
Figure imgf000044_0003
, wherein n is an integer from 0 to 5.
[0085] In other embodiments, B is
Figure imgf000044_0005
, as described above, and
Figure imgf000044_0004
is
Figure imgf000044_0006
, wherein n is an integer from 0 to 11.
[0086] In still other embodiments B is
Figure imgf000044_0008
, as described above,
Figure imgf000044_0007
Figure imgf000044_0009
, ) are present, it should be understood that they may be optionally different unless otherwise indicated.
[0087] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, 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. [0088] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, B is phenyl, and n is an integer from 0 to 5. Thus, for example, in some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000045_0001
Figure imgf000045_0002
. When multiple instances of a substituent (for example, RcS) are present, it should be understood that they may be optionally different unless otherwise indicated.
[0089] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000045_0003
[0090] In some embodiments, the compound of Formula (III) is a compound of Formula (III-A-i):
Figure imgf000046_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0091] In some embodiments, the compound of Formula (III) is a compound of Formula (III-A-iii):
Figure imgf000046_0002
-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0092] In some embodiments of the compound of Formula (III-A-i) or Formula (III-A-iii), 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, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
[0093] In some embodiments of the compound of Formula (III- A), Formula (III-A-i), Formula (III-A-ii), or Formula (III-A-iii), or a stereoisomer or pharmaceutically acceptable
salt thereof,
Figure imgf000047_0001
integer from 0 to 6. In other
embodiments,
Figure imgf000047_0002
integer from 0 to 6.
[0094] In some embodiments, the compound of Formula (III) is a compound of Formula (III-B-iii):
Figure imgf000047_0003
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(RC49)2-, -S(0)I-, -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III). [0095] In some embodiments, the compound of Formula (III) is a compound of Formula (III-B-i):
Figure imgf000048_0001
iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(RC49)2-— S(0)— , -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0096] In some embodiments of the compound of Formula (III-B-i) or Formula (III-B-iii), 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, d is 0. In other embodiments, d is 1. In still further embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5.
[0097] In certain embodiments of the compound of Formula (III-B-i) or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, Y is -C(Rc49)2-, wherein each Rc49 is independently hydrogen or Rc4. In certain embodiments, Y is -CH2-. In other embodiments, Y is -CHRc4-. In some embodiments, Y is -C(Rc4)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(Rc49)-, wherein Rc49 is hydrogen or Rc4. For example, in certain embodiments, Y is -NH-. In some embodiments, Y is -NRc4-.
[0098] In some embodiments of the compound of Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000049_0001
integer from 0 to 6. In other
embodiments,
Figure imgf000049_0002
integer from 0 to 6.
[0099] In some embodiments of the compound of Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, d is an integer from 0 to 5. In other embodiments, d is an integer from 0 to 4, or from 0 to 3, or from 0 to 2. In some
embodiments, d is 0 or 1. In certain embodiments, d is 1. In other embodiments, d is 2. In some embodiments, d is 3. In still other embodiments, d is 4. In certain embodiments, d is 5.
[0100] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rc4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRc8Rc9, -ORcl°, =0, -SRc51, and -S02Rc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo. In certain embodiments, each Rc4 is independently selected from the group consisting of halo, (Ci-Ce)alkyl, (C3- C6)cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-Cio)aryl, 5- to lO-membered heteroaryl, -NO2, -CN, -SO2NH2, -NRc8Rc9, -ORcl°, =0, SRc51, and -S02Rcl1, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo. In some embodiments, each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl. In certain embodiments, each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C3- C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, or 3- to lO-membered
haloheterocycloalkyl. In some embodiments, each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is
independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In certain embodiments, each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, (Ci-C6)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)halocycloalkyl. In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rc4 is independently selected from the group consisting of fluoro, chloro, bromo, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3- C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to 6-membered heterocycloalkyl, -NO2, -CN, -SO2NH2, -NH2, - H(Ci-C6)alkyl, -N((Ci-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 Rc4 is independently selected from the group consisting of fluoro, chloro, bromo, (Ci-C6)alkyl, (Ci- C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In certain embodiments, at least one Rc4 is fluoro, chloro, bromo, (Ci-C6)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 Rc4 is fluoro, chloro, bromo, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, or -0-(Ci- C6)haloalkyl. In certain embodiments, at least one Rc4 is fluoro, chloro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2, or -CF3.
[0101] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, two to four Rc4, 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 Rc4, 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 Rc4, 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 Rc4 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRc8Rc9, _ORcl°, =0, -SRc51, and -S02Rcl1, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more halo.
[0102] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CN, -SFs, -NO2, =0, -ORc27, and
-NRC28Rc29; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, -O-alkyl, -OH, -O-haloalkyl, =0, -CN, -NH2, and -SFs. In some embodiments, each Rc6 is independently selected from the group consisting of halo, (Ci-Cs)alkyl, (C2-C6)alkynyl, (C3-Cs)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, 5- to 8-membered heteroaryl, -CN, -SFs, -NO2, =0, -ORc27, and -NRC28Rc29; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (Ci-Ce)alkyl, -0-(Ci-C6)alkyl, -OH, -0-(Ci-C6)haloalkyl, =0, -CN, -NH2, and -SFs. In some embodiments, each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -CN, -SFs, -NO2, =0, -ORc27, and -NRc28Rc29; wherein each alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, -O- alkyl, -OH, -O-haloalkyl, =0, -CN, -NH2, and -SFs. In some embodiments, each Rc6 is independently selected from the group consisting of halo, (Ci-C6)alkyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, -CN, -SFs, -NO2, =0, -ORc27, and -NRC28Rc29; wherein each alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (Ci-C6)alkyl, -0-(Ci-C6)alkyl, -OH, -0-(Ci-C6)haloalkyl, =0,
-CN, -ML·, and -SFs.
[0103] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rc6 is independently selected from the group consisting of halo, alkyl, haloalkyl, -ORc27, and -NRc28Rc29, wherein each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl. In some embodiments, each Rc6 is independently halo, (Ci-C6)alkyl, (Ci- C6)haloalkyl, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, or -NRc28Rc29, wherein Rc28 and Rc29 are independently hydrogen, (Ci-C6)alkyl, or (Ci-C6)haloalkyl. In some embodiments, at least one Rc6 is chloro, fluoro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -ML·, -MI(CH3), -N(CH3)2,
-M¾CH2CH3), -N(CH2CH3)2, or -N(CH3)(CH2CH3). In some embodiments, each Rc6 is independently chloro, fluoro, methyl, ethyl, propyl, -OH, methoxy, ethoxy, propoxy, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -ML·, -MI(CH3), -N(CH3)2,
-MI(CH2CH3), -N(CH2CH3)2, or -N(CH3)(CH2CH3). In some embodiments, each Rc6 is independently fluoro, chloro, methoxy, methyl, -CF3, -OH, or -N(CH3)2. In some embodiments, at least one Rc6 is chloro, fluoro, methoxy, methyl, -OH, -CF3, or -N(CH3)2.
[0104] In some embodiments of the compound of Formula (III), Formula (III-A), or Formula (III-B), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000052_0001
[0105] In some embodiments of the compound of Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000053_0001
[0106] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rc5 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, NO2, CN, S02NRc52Rc53,
-NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16. In some embodiments, one or more Rc5 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; and (Ci- )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, -NRc21Rc22, and -CN. In certain embodiments, one or more Rc5 is independently selected from the group consisting of halo, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In certain embodiments, each Rc5 is independently selected from the group consisting of halo, (Ci- C6)alkyl, (Ci-Ce)haloalkyl, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, and -CN. In some embodiments, one or more Rc5 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2,
CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3, -NO2, phenyl, =0, -SO2NH2, -CN, cyclopropyl, cyclohexyl, and -OCH2CCH. In some embodiments, at least one Rc5 is halo, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, or -CN. In certain embodiments, at least one Rc5 is chloro, fluoro, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F, -CHF2, -CF3, -OCH2F,
-OCHF2, -OCF3, or -CN. In certain embodiments, at least one Rc5 is chloro, fluoro, -OCH3, or -CN. In some embodiments, each Rc5 is independently chloro, fluoro, -OCH3, or -CN. In some embodiments, at least one Rc5 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCI3, -CH2Br, -CHBr2, -CBr3, -CH2I, -CHFI2, -CI3, -OCH2CI, -OCHCb, -OCCh, -OCFhBr, -OCHBr2, -OCBr3, -OCH2I, -OCHFL·, -OCI3, -OCH2F, -OCHF2, -OCF3, -NO2, phenyl, =0, -SO2NH2, -CN, cyclopropyl, cyclohexyl, and -OCH2CCH.
[0107] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 is alkyl, wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORc20, =0, -NRC21Rc22, -CN, -SFs, -S02NRc58Rc59, -SRc60, -S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rc62 is independently (C3-C6)cycloalkyl, 3- to 8-membered
heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Rc5 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, -ORc20, =0, -NRc21Rc22, -CN, -SF5, -S02NRC58Rc59, -SRc60, and -S02Rc61. 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-Cs)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In further embodiments, the alkyl is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In still other embodiments, the alkyl is (Ci-C4)alkyl, wherein the alkyl is unsubstituted or substituted as described above. In some embodiments, at least one Rc5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, difluoromethyl, or fluoromethyl.
[0108] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 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, -ORc17, =0, -NRcl8Rc19, -CN ,-SFS, -S02NRC54Rc55, -SRc56, -S02Rc57, and Rc23, wherein each Rc23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, each Rc23 is independently (Ci-C6)alkyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, Rc23 is unsubstituted alkyl. In some embodiments, Rc23 is unsubstituted (Ci- C6)alkyl. In other embodiments, Rc23 is alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkynyl, cycloalkyl, heterocycloalkyl, -NRc24Rc25, -ORc26, and -SFs. In certain embodiments, Rc23 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,
-NRC24Rc25, -ORc26, and -SFs. In some embodiments, Rc23 is (Ci-C6)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRc24Rc25, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In certain embodiments, Rc23 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
[0109] In certain embodiments of the compound of Formula (III), Formula (III-A),
Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 is cycloalkyl, wherein each cycloalkyl is independently substituted with one or more substituents independently selected from the group consisting of halo, -ORc17, =0, -NRcl8Rc19, -CN -SFS, -S02NRC54Rc55, -SRc56, -S02Rc57, and Rc23, wherein each Rc23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rc23 is independently (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, 3- to 8- membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Rc5 is cycloalkyl, wherein the cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -ORc17, =0, -NRC18Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56, and -S02Rc57. In some embodiments, at least one Rc5 is unsubstituted cycloalkyl. [0110] In certain embodiments, at least one Rc5 is unsubstituted (C3-C6)cycloalkyl. In some embodiments, at least one Rc5 is cycloalkyl substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, halo, -ORc17, =0, -NRcl8Rc19, -CN, -SFs, -SC>2NRc54Rc55, -SRc56, and -S02Rc57. In certain embodiments, at least one Rc5 is (C3-C6)cycloalkyl substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -ORc17, =0, -NRcl8Rc19, -CN, -SFs, -SC>2NRC54Rc55, -SRc56, and -S02Rc57. In certain embodiments, one or more Rc5 is (C3-C6)cycloalkyl substituted with one or more substituents independently selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, halo, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, =0, -NRcl8Rc19, -CN, -SFs,
-S02NRC54Rc55, -SRc56, and -S02Rc57. In some embodiments, at least one Rc5 is (C3- C6)cycloalkyl substituted with one or more substituents independently selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C6-Cio)aryl, 3- to 6- membered heteroaryl, halo, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, =0, -NRcl8Rc19, -CN, and -SFs.
[0111] In certain embodiments of the compound of Formula (III), Formula (III-A),
Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 is aryl, wherein each aryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORc17, =0, -NRC18Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56, -S02Rc57, and Rc23, wherein each Rc23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rc23 is independently (Ci-C6)alkyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Rc5 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 Rc23. In some embodiments, Rc23 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rc23 is (Ci-C6)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NRC24Rc25, -ORc26, and -SFs. In some embodiments, Rc23 is (Ci-C6)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRc24Rc25, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci-C6)haloalkyl. In some embodiments, at least one Rc5 is unsubstituted aryl.
[0112] In certain embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 is heteroaryl, wherein each heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORc17, =0, -NRcl8Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56, -S02Rc57, and Rc23, wherein each Rc23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rc23 is independently (Ci-C6)alkyl, (C3- C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (C6-Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Rc5 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 Rc23. In some embodiments, Rc23 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rc23 is (Ci-C6)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NRc24Rc25, -ORc26, and -SFs. In some embodiments, Rc23 is (Ci-C6)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRc24Rc25, -SFs, -OH, -0-(Ci-C6)alkyl, and -0-(Ci- C6)haloalkyl. In some embodiments, at least one Rc5 is unsubstituted heteroaryl.
[0113] In certain embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 is heterocycloalkyl, wherein each heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORc17, =0, -NRcl8Rc19, -CN, -SFs,
-S02NRC54Rc55, -SRc56, -S02Rc57, and Rc23, wherein each Rc23 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rc23 is independently (Ci-C6)alkyl, (C3-C6)cycloalkyl, 3- to 8-membered heterocycloalkyl, (Cr>- Cio)aryl, or 3- to 8-membered heteroaryl. In some embodiments, at least one Rc5 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 Rc23. In some embodiments, Rc23 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rc23 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -NRc24Rc25, -ORc26, and -SFs. In some embodiments, Rc23 is (Ci-C6)alkyl substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRc24Rc25, -SFs, -OH, -0-(Ci-C6)alkyl, and - 0-(Ci-C6)haloalkyl. In some embodiments, at least one Rc5 is unsubstituted heterocycloalkyl.
[0114] In certain embodiments of the compound of Formula (III), Formula (III-A),
Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rcl2, Rcl3, Rcl4, Rcl5, Rcl6, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, Rc52, Rc53, Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl. In some embodiments, each Rcl2, Rcl3, Rcl4, Rcl5, Rcl6, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, Rc52,
RCSS, Rc54 RCS5; RC56 RC5T RCS8> RC59 RC6O and RC6i independently hydrogen, (C1-C6)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 (III), Formula (III-A),
Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each Rcl5, Rcl6, Rcl7, Rcl8, Rcl9, Rc52, Rc53, Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl. In some embodiments, each Rcl5, Rcl6, Rcl7, Rcl8, Rcl9, Rc52, Rc53, Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, Rc60, and Rc61 is independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)halocycloalkyl. In certain embodiments, each Rci2, ^c 13 RC2O C2 I ^ and Rc22 independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl. In some embodiments, each Rcl2, Rcl3, Rc20, Rc21, and Rc22 is
independently hydrogen, (C i-G,)alkyl, (C3-C6)cycloalkyl, 3- to lO-membered
heterocycloalkyl, 3- to lO-membered heteroaryl, or (C6-Cio)aryl. In some embodiments, each Rcl4 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl. In certain embodiments, each Rcl4 is independently hydrogen, (Ci-C6)alkyl, (C3- C6)cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-Cio)aryl, 3- to lO-membered heteroaryl, or (C3-C6)alkynyl.
[0116] In certain embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rc62 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, -NRc24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo,
-CN, -SFs, =0, -NRC40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63;
wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 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.
[0117] In certain embodiments each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rc62 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, =0, -CN, (C6-Cio)aryl, 5- to lO-membered heteroaryl, (Ci-Ce)alkyl, (C2-Ce)alkynyl, (C3- C6)cycloalkyl, 5- to 10-membered heterocycloalkyl, -NRc24Rc25, -ORc26, 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-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRc42C(0)Rc43, -ORc44, and Rc63; wherein each Rc63 is independently (C3-C6)cycloalkyl, 5- to 10- membered heterocycloalkyl, (C6-Cio)aryl, or 5- to lO-membered heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -ML·, -SFs, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl.
[0118] In certain embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of Rc62 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,
-NRc24Rc2-\ -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRC40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63;
wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 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.
[0119] In some embodiments, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of Rc62 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-C6)alkyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, 5- to lO-membered heterocycloalkyl, -NRc24Rc25, -ORc26, 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-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, - Rc42C(0)Rc43, -ORc44, and Rc63;
wherein each Rc63 is independently (C3-C6)cycloalkyl, 5- to 10- membered heterocycloalkyl, (C6-Cio)aryl, or 5- to lO-membered heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, ML·, SFs, OH, 0-(Ci-C6)alkyl, 0-(Ci-C6)haloalkyl, halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl.
[0120] In some embodiments, each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl. In some embodiments, each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, (C i-Cr,)alkyh or (Ci-C6)haloalkyl
[0121] In certain embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, at least one Rc5 is:
Figure imgf000061_0001
wherein:
Rc30 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, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORc33, -SFs, and -MIc34Rc35;
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, -ORc36,
-NRC45Rc46,
-NRC47C(0)Rc48, 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 -SF5;
each Rc31 and Rc32 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, -ORc37, and -NRc38Rc39;
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 Rc31 and one Rc32 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 Rc33, Rc34, Rc35, Rc36, Rc37, Rc38, Rc39, Rc45, Rc46, Rc47, and Rc48 is independently hydrogen, alkyl, or haloalkyl;
and q is 1 or 2.
[0122] In some embodiments, each Rc33, Rc34, Rc35, Rc36, Rc37, Rc3S, Rc39, Rc45, Rc46, Rc47, and Rc48 is independently hydrogen, (Ci-C6)alkyl, or (Ci-C6)haloalkyl. In certain embodiments, each Rc33, Rc34, Rc35, Rc36, Rc37, Rc38, Rc39, Rc45, Rc46, Rc47, and Rc48 is independently hydrogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, or halobutyl.
[0123] In some embodiments, Rc30 is hydrogen. In other embodiments, Rc30 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, -ORc33, -SFs, and -NRc34Rc35. In still other embodiments, Rc30 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, -ORc33, -SFs, and -NRc34Rc35.
[0124] In certain embodiments, Rc30 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, -ORc36, -NRc45Rc46,
-NRC47C(0)Rc48, 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-C6)alkyl, (Ci-C6)haloalkyl, halo, -SFs, =0, -OH, -0(Ci-Cs)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.
[0125] In some embodiments, Rc30 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-C6)alkyl, -SFs, -OH, -0(Ci-C6)alkyl, =0, -NRC45Rc46, and -NRc47C(0)Rc48. In some embodiments, Rc30 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-Cr,)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, Rc30 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with one or more (C6-Cio)aryl or 3- to 6-membered heteroaryl.
[0126] In certain embodiments, Rc30 is unsubstituted (Ci-C6)alkyl. In other embodiments, Rc30 is (Ci-C6)alkyl substituted with 3- to 6-membered heteroaryl. In other embodiments, Rc30 is (Ci-C6)alkyl substituted with phenyl, wherein the phenyl is unsubstituted or substituted with one more substituents independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, -OH, -0(Ci-Ce)alkyl, -SFs, -NHC(0)H, and -NHC(O)- (Ci-C6)alkyl. In other embodiments, Rc30 is (Ci-C6)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, - HC(0)-(Ci-C6)alkyl, =0, -NIL·, and -NH(Ci-C6)alkyl.
[0127] In some embodiments, Rc30 is (Ci-C6)alkyl substituted with (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, -OH, and -0(Ci- C6)alkyl. In other embodiments, Rc30 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.
[0128] In some embodiments, Rc30 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, Rc30 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.
[0129] In some embodiments, Rc30 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, Rc30 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.
[0130] In still further embodiments, Rc30 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, Rc30 is phenyl, wherein the phenyl is unsubstituted or substituted with one or more (Ci-C6)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, - HC(0)H, -NHC(0)-(Ci-C6)alkyl, =0, -NH2, and -NH(Ci-C6)alkyl.
[0131] In still further embodiments, Rc30 is heteroaryl, wherein the heteroaryl 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(O)- (Ci-C6)alkyl, and 3- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with =0.
[0132] In some embodiments, Rc30 is alkynyl. In certain embodiments, Rc30 is (C2- C6)alkynyl.
[0133] In certain embodiments, Rc is
Figure imgf000065_0001
[0134] In certain embodiments, Rc30 is:
Figure imgf000066_0001
[0135] In some embodiments, Rc31 and Rc32 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, Rc31 and Rc32 attached to the same carbon form an unsubstituted cyclopropyl or cyclobutyl. In some embodiments, Rc31 and Rc32 attached to the same carbon form a cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl are substituted with one or more halo.
[0136] In some embodiments, each Rc31 and Rc32 is hydrogen. In some embodiments, at least one Rc31 or one Rc32 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, -ORc37, and -NRc38Rc39, 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 Rc31 or one Rc32 is alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, 3- to lO-membered heterocycloalkyl, aryl, 3- to 6-membered heteroaryl, -OH, -0-(Ci-C6)alkyl, -0-(Ci-C6)haloalkyl, -Nth, -NH(Ci-C6)alkyl, -N((Ci- C6)alkyl)((Ci-C6)alkyl). In some embodiments, one Rc31 or one Rc32 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 Rc31 or one Rc32 is (C i-Cr,)alkyl, wherein the alkyl is unsubstituted or substituted with fluoro, chloro, (C3-C6)cycloalkyl, (C3)halocycloalkyl, or -OH. In some embodiments, one Rc31 or one Rc32 is ethyl substituted with difluorocy cl opropy 1.
[0137] In some embodiments, at least one Rc31 or Rc32 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 Rc31 or Rc32 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-C6)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 Rc31 or Rc32 is alkyl substituted with 5- to 6-membered heteroaryl.
[0138] In some embodiments q is 1. In still other embodiments, q is 2. In some embodiments, q is 1, and one of Rc31 and Rc32 is hydrogen. In some embodiments, q is 1 and Rc31 is hydrogen. In other embodiments, q is 2, and one Rc31 and two Rc32 are hydrogen. In other embodiments, q is 2, and two Rc31 and one Rc32 are hydrogen. In some embodiments, q is 2, and two Rc31 and three Rc32 are hydrogen. In some embodiments, q is 2, and three Rc31 and two Rc32 are hydrogen.
[0139] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-ii), Formula (III-B), or Formula (III-B-ii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000067_0001
[0140] In some embodiments of the compound of Formula (III-A-i) or Formula (III-B-i), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000067_0002
[0141] In some embodiments of the compound of Formula (III-A-iii) or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure imgf000068_0001
[0142] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(O)-, -S(0)2-, -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2- In some embodiments, X is -S(0)2-, -C(O)-, or -C(Rc7)2-. In certain embodiments, X is -S(O)-,
— S(0)2— , or -S(0)NRc50-. In other embodiments, X is -C(S)-, -C(O)-, or -C(Rc7)2-.
[0143] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(O)-.
[0144] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(0)2-
[0145] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(0)NRc50-, wherein Rc50 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, Rc50 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, Rc50 is hydrogen. In other embodiments, Rc50 is unsubstituted (Ci-C6)alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In still other embodiments, Rc50 is (Ci-C6)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, Rc50 is (Ci-Ce)alkyl substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C3-C6)cycloalkyl, and =0.
[0146] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -C(S)-.
[0147] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -C(O)-.
[0148] In some embodiments, of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -C(Rc7)2-, wherein each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl. In certain embodiments, each Rc7 is independently hydrogen, halo, (Ci-C6)alkyl, or (Ci-C6)haloalkyl. In some embodiments, each Rc7 is independently hydrogen, chloro, fluoro, methyl, ethyl, propyl, -CFkF, -CHF2, or -CF3. In some embodiments, each Rc7 is H, and X is -CH2-.
[0149] In some embodiments of the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, X is -S(0)2-, -C(O)-, or -CH2-. [0150] In some embodiments, the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii) is:
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000071_0002
stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0151] In some embodiments, the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii) is:
Figure imgf000071_0003
Figure imgf000072_0001
Figure imgf000073_0001
stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0152] The compounds described herein, including compounds of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (PI-B), Formula (III-B-i), Formula (III-B-ii), or Formula (IP-B-iii), or their stereoisomers or pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, or other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( R )- or (5)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), or ( R )- and (ri)-i somers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid
chromatography (HPLC). While Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (TTT-B) Formula (III-B-i), Formula (III-B-ii), and Formula (III-B-iii), and compounds of these formulae disclosed herein depict -CN and Z in a cis orientation, as
Figure imgf000073_0002
, the stereoisomers of these formulae and compounds with -CN
and Z in a trans orientation, as CN 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.
[0153] “Pharmaceutically acceptable salt” includes a salt which is generally safe, non toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. Such salts may include acid addition salts and base addition salts. Acid addition salts may be formed with inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, 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.
[0154] Unless otherwise stated, the compounds provided herein, including compounds of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or their stereoisomers or pharmaceutically acceptable salts, also include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds may have the present structures except for the replacement of a hydrogen by a deuterium (D or 2H) or tritium (3H), or the replacement of a carbon-l2 by a carbon-l3 (13C) or carbon-l4 (14C).
[0155] The compounds disclosed herein, such as a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (PI-B), Formula (III-B-i), Formula (III-B-ii), or Formula (IP-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, may be prepared, for example, through the reaction route depicted in General Scheme III- 1.
General Scheme III-l
Figure imgf000075_0001
[0156] General Scheme III-l provides one route to prepare a compound disclosed herein, such as a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B- iii), or a stereoisomer or pharmaceutically acceptable salt thereof. In this scheme, compound PI-102 is combined with 2-cyanoacetic acid (compound III-104), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC HCI),
hydroxybenzotriazole (HOBt), triethylamine (Et3N), and solvent (such as dichloromethane, DCM), and this mixture stirred at room temperature for 18 hours to produce compound IH- 106. This compound is then combined with trifluoroacetic acid (TFA) and solvent (such as DCM) and stirred from 0 °C to room temperature to remove the BOC protecting group and produce compound III-108. Compound PI-108 is combined with EtiN, solvent (such as DCM), and an RB-SChCl reactant, wherein the RB is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. This mixture is stirred at room temperature for 4 hours to produce compound III-110. This compound is then combined with piperidine (30 mol%), a solvent (such as dimethylsulfoxide, DMSO), and Rz-C(0)H, wherein Rz is hydrogen or substituted or unsubstituted alkyl, cycloalkyl, aryl, or heteroaryl, and this mixture stirred at 100 °C for 18 h to produce compound III-112, which is an example of a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
[0157] While General Scheme III- 1 depicts the synthesis of compounds of Formula (PI), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or
pharmaceutically acceptable salt thereof, 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; or wherein Rcl, Rc2, and Rc3 are other than hydrogen, may also be synthesized using a route analogous to General Scheme III- 1. Furthermore, in some embodiments of the 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 or time may be adjusted. The reactants, solvents, and other compounds used to prepare a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or
pharmaceutically acceptable salt thereof, by following General Scheme III- 1 , or by another route, may be commercially available or may be prepared following organic chemical techniques.
[0158] Further provided herein is a pharmaceutical composition comprising a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient may include, for example, an adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans. Pharmaceutically acceptable excipients may include, but are not limited to, water, NaCl, normal saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors.
II. Methods of Treatment
[0159] 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 (III), Formula (TTT-A) Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
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 (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a
stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 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.
[0160] Also provided herein is the use of a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
[0161] Further provided herein is a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
[0162] 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 to a mutation or dysregulation of human K-Ras4b. In certain embodiments, the disorder is related to aberrant K-Ras4b signaling pathway activity.
[0163] In some embodiments, the disorder is neurofibromatosis type 1 (NF1), Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome. In some embodiments, the disorder is neurofibromatosis type 1 (NF 1 ). NF1 is a disorder that predisposes subjects to cancer. Subjects with NF1 are at greater risk than the general population for developing malignancies, which may include pediatric malignancies or adult malignancies. Pediatric malignancies may include optic pathway glioma, rhabdomyosarcoma, neuroblastoma, and juvenile myelomonocytic leukemia. Adult malignancies may include malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas,
pheochromocytomas, and breast cancer.
[0164] 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, the cancer is related to the KRAS gene, for example a cancer associated with a mutation of the KRAS gene or dysregulation of the KRAS gene. Mutation or dysregulation of K-Ras or KRAS may include mutation or dysregulation of human K-Ras4a and/or human K-Ras4b. In some embodiments, the cancer is related to the K-Ras (for example, human K-Ras4a and/or human K-Ras4b) signaling pathway activity, for example cancer related to aberrant K-Ras signaling pathway activity. In some embodiments, the cancer is related to mutation or dysregulation of human K-Ras4b. In certain embodiments, the cancer is related to aberrant K-Ras4b signaling pathway activity.
[0165] 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 (III), Formula (III-A), Formula (III-A-i), Formula (IP-A- ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer. 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 (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III- B), Formula (III-B-i), Formula (III-B-ii), or Formula (PI-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, is co-administered with one or more
chemotherapeutic agents to a subject in need thereof.
[0166] 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 (III), Formula (III-A), Formula (III-A-i),
Formula (III-A-ii), Formula (IP-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof. In still another aspect, provided herein is a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, 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 (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for 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. Reduction of the level of K-Ras may be evaluated, for example, by immunoblot of a biological sample using one or more specific anti-K-Ras antibodies, or by mass spectrometry-based methods.
[0167] In some embodiments, administering a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, to a subject may block one or more post-translational processing steps of a K-Ras precursor (such as K-Ras4a precursor or K-Ras4b precursor). This unprocessed precursor may then be degraded by the body, thus reducing the level of K-Ras protein. In some embodiments, the compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, covalently binds to the C185 amino acid residue of a K-Ras precursor (such as K-Ras4a precursor or K- Ras4b precursor) to block one or more post-translational modifications. In certain embodiments, the post-translational modification that is blocked is farnesylation.
[0168] 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 (III), Formula (III-A), Formula (III-A-i),
Formula (III-A-ii), Formula (IP-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof. In still another aspect, provided herein is a compound of Formula (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or pharmaceutically acceptable salt thereof, 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 (III), Formula (III-A), Formula (III-A-i), Formula (III-A-ii), Formula (III-A-iii), Formula (III-B), Formula (III-B-i), Formula (III-B-ii), or Formula (III-B-iii), or a stereoisomer or
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the activity of a K-Ras protein in a subj ect 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.
[0169] In some embodiments, both the activity of K-Ras and the level of K-Ras are reduced in a subject in need thereof.
[0170] “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. [0171] 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.
[0172] “ 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
[0173] Embodiment I- 1. A compound of Formula (III):
Figure imgf000081_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2-, -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2-;
each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
Rc50 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;
Rcl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NC , -CN, -SO2NH2, -NRc8Rc9, -ORcl°, and -S02Rc11, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NCh, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -SCkRc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo; or Rc2 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc3 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rc2 and Rc3, 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 Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
S02NRc52Rc53, -NRC12Rc13, ORc14, S02Rc15, =0, and SRc16;
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, -ORc17, =0, -NRC18Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56,
-S02Rc57, and Rc23, wherein each Rc23 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, -ORc20, =0, -NRC21Rc22, -CN, -SFs, -S02NRC58Rc59, -SRc60,
-S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rcl2 Rcl 3 Rc^ Rc 33 Rcl6 J^cl7 Rc^ Rcl9 J^c20 j^c2l j^c22 j^c52 j^c53
Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2,
RGB RC RC P RC18^ RCW RC205 RC2 1 Rc22 and Rc23^ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rc62 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,
-NRC24Rc25, -ORc26, and
-SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 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; and each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -CN, -SFs, -NO2, =0, -ORc27, and -NRc28Rc29; wherein each alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, -O- alkyl, OH, O-haloalkyl, =0, CN, NH2, and SFs; and each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13;
n is an integer from 0 to 11; and
v is an integer from 0 to 11. [0174] Embodiment 1-2. The compound of Embodiment 1-1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Z is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2- -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2-;
each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
Rc50 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;
Rcl is hydrogen, alkyl, or cycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRc8Rc9, -ORcl°, and -S02Rc11, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -S02Rc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is independently unsubstituted or substituted with one or more halo;
each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, or halocycloalkyl;
or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; or Rc2 and one Rc4, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rc2 and Rc3, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl;
each Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRc52Rc53, -NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16,
wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -ORc17, =0, -NRcl8Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56, -S02Rc57, and Rc23, wherein each Rc23 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, -SF5, and Rc23, wherein each Rc23 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, -ORc20, =0, -NRC21Rc22, -CN, -SFs, -S02NRC58Rc59, -SRc60,
-S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
6 Ch Rcl 5 Rcl6 Rcl7 J^cl8 j^cl9 j^c52 j^c53 j^c54 j^c55 j^c56 j^c57 j^c58 j^c59
RcS0, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
each Rcl2, Rcl3, Rc20, Rc21, and Rc22 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, or aryl; each Rcl4 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl 3. Rcl4, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl of Rc62 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,
-NRC24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NFb, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, haloalkyl, ORc27, and NRc28Rc29, wherein each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and
v is an integer from 0 to 11.
[0175] Embodiment 1-3. The compound of Embodiment 1-1 or 1-2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is aryl or heteroaryl. [0176] Embodiment 1-4. The compound of any one of Embodiments 1-1 to 1-3, wherein the compound is of Formula (III-A):
Figure imgf000088_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7; and
B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
[0177] Embodiment 1-5. The compound of any one of Embodiments 1-1 to 1-4, wherein the compound is of Formula (III-A-ii):
Figure imgf000088_0002
-ii),
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
B, X, Rc4, Rc5, Rc6, and n are as defined for Formula (III).
[0178] Embodiment 1-6. The compound of any one of Embodiments 1-1 to 1-3, wherein the compound is of Formula (III-B):
Figure imgf000089_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(RC49)2- -S(0)r- -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2; and
B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
[0179] Embodiment 1-7. The compound of any one of Embodiments 1-1 to 1-3, or 1-6, wherein the compound is of Formula (III-B-ii):
Figure imgf000089_0002
ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(Rc49)2-, -S(0)r- -O-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4 ;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
B, X, Rc4, Rc5, Rc6, and n are as defined for Formula (III).
[0180] Embodiment 1-8. The compound of Embodiment 1-6 or 1-7, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CH2-. [0181] Embodiment 1-9. The compound of any one of Embodiments 1-1 to 1-3, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
[0182] Embodiment 1-10. The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
[0183] Embodiment 1-11. The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 9- or lO-membered bicyclic heteroaryl comprising one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
[0184] Embodiment 1-12. The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C9-Cio)bicyclic aryl.
[0185] Embodiment 1-13. The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C5-Cio)cycloalkyl.
[0186] Embodiment 1-14. The compound of any one of Embodiments 1-1 to 1-13, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one or more Rc5 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; and (Ci-C4)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, -NRc21Rc22, and -CN.
[0187] Embodiment 1-15. The compound of any one of Embodiments 1-1 to 1-9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5. [0188] Embodiment 1-16. The compound of any one of Embodiments 1-1 to 1-4, 1-6, or I- 9 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 5- membered heteroaryl.
[0189] Embodiment 1-17. The compound of Embodiment 1-16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is pyrazolyl, thiophenyl, furanyl, or oxazolyl.
[0190] Embodiment 1-18. The compound of any one of Embodiments 1-1 to 1-4, 1-6, or I- 8 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 9- membered heteroaryl.
[0191] Embodiment 1-19. The compound of Embodiment 1-18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is benzothiophenyl or indolyl.
[0192] Embodiment 1-20. The compound of any one of Embodiments 1-1 to 1-4, 1-6, or I- 8 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 6- membered heteroaryl.
[0193] Embodiment 1-21. The compound of any one of Embodiments 1-1, 1-2, 1-4, 1-6, or 1-8 to 1-15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is alkyl or cycloalkyl.
[0194] Embodiment 1-22. The compound of any one of Embodiments 1-1 to 1-5, 1-9, or I- 14, wherein the compound is of Formula (III-A-i):
Figure imgf000091_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0195] Embodiment 1-23. The compound of Embodiments 1-1 to 1-3, 1-6 to 1-9, or 1-14, wherein the compound is of Formula (III-B-i):
Figure imgf000092_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(Rc49)2-,— S(0)— , -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0196] Embodiment 1-24. The compound of any one of Embodiments 1-1 to 1-5, 1-9, or I- 14, wherein the compound is of Formula (III-A-iii):
Figure imgf000092_0002
-iii) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III). [0197] Embodiment 1-25. The compound of Embodiments 1-1 to 1-3, 1-6 to 1-9, or 1-14, wherein the compound is of Formula (III-B-iii):
Figure imgf000093_0001
iii),
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(RC49)2-,— S(0)— , -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
[0198] Embodiment 1-26. The compound of any one of Embodiments 1-1 to 1-25, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rc5 is:
Figure imgf000093_0002
wherein:
Rc30 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, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORc33, -SFs, and -NRc34Rc35; 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, -ORc36,
-NRc45Rc46, -NRC47C(0)Rc48, 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 Rc31 and Rc32 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, -ORc37, and _ NRC38Rc39;
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 Rc31 and one Rc32 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 Rc33, Rc34, Rc35, Rc36, Rc37, Rc38, Rc39, Rc45, Rc46, Rc47, and Rc48 is independently hydrogen, alkyl, or haloalkyl;
and q is 1 or 2.
[0199] Embodiment 1-27. The compound of Embodiment 1-26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and Rc31 is hydrogen.
[0200] Embodiment 1-28. The compound of any one of Embodiments 1-1 to 1-27, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rc5 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 Rc23.
[0201] Embodiment 1-29. The compound of Embodiment 1-28, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rc23 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
[0202] Embodiment 1-30. The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
[0203] Embodiment 1-31. The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
[0204] Embodiment 1-32. The compound of any one of Embodiments 1-1 to 1-29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CH2-
[0205] Embodiment 1-33. The compound of any one of Embodiments 1-1 to 1-21 or 1-26 to 1-32, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
[0206] Embodiment 1-34. The compound of any one of Embodiments 1-1 to 1-3, 1-9 to I- 21, or 1-26 to 1-32, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
[0207] Embodiment 1-35. The compound of any one of Embodiments 1-4 to 1-8, or 1-22 to 1-25, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.
[0208] Embodiment 1-36. The compound of any one of Embodiments 1-1 to 1-35, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rc6 is chloro, fluoro, methoxy, methyl, -OH, -CF3, or -N(CH3)2.
[0209] Embodiment 1-37. The compound of Embodiment 1-1, wherein the compound is:
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000097_0002
stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
[0210] Embodiment 1-38. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0211] Embodiment 1-39. A method of reducing the level of a K-Ras protein in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0212] Embodiment 1-40. The method of Embodiment 1-39, wherein the K-Ras protein is human K-Ras4b.
[0213] Embodiment 1-41. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0214] Embodiment 1-42. The method of Embodiment 1-41, wherein the disorder is cancer. [0215] Embodiment 1-43. The method of Embodiment 1-42, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
[0216] Embodiment 1-44. The method of Embodiment 1-41, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
[0217] Embodiment 1-45. The method of any one of Embodiments 1-41 to 1-44, wherein the disorder is associated with a mutation of K-Ras.
[0218] Embodiment 1-46. Use of a compound of any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof.
[0219] Embodiment 1-47. The use of Embodiment 1-46, wherein the K-Ras protein is human K-Ras4b.
[0220] Embodiment 1-48. Use of a compound of any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
[0221] Embodiment 1-49. The use of Embodiment 1-48, wherein the disorder is cancer.
[0222] Embodiment 1-50. The use of Embodiment 1-49, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
[0223] Embodiment 1-51. The use of Embodiment 1-48, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome. [0224] Embodiment 1-52. The use of any one of Embodiments 1-48 to 1-51, wherein the cancer is associated with a mutation of K-Ras.
[0225] Embodiment 1-53. A compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
[0226] Embodiment 1-54. The compound for use of Embodiment 1-53, wherein the K-Ras protein is human K-Ras4b.
[0227] Embodiment 1-55. A compound according to any one of Embodiments 1-1 to 1-37, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
[0228] Embodiment 1-56. The compound for use of Embodiment 1-55, wherein the disorder is cancer
[0229] Embodiment 1-57. The compound for use of Embodiment 1-56, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma,
rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
[0230] Embodiment 1-58. The compound for use of Embodiment 1-55, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
[0231] Embodiment 1-59. The compound for use of any one of Embodiments 1-55 to 1-58, wherein the cancer is associated with a mutation of K-Ras.
EXAMPLES
[0232] The following Examples are merely illustrative and are not meant to limit any aspects of the present disclosure in any way. Example III-l: Synthesis of tert-butyl (R)-3-((2-cyanoacetamido)methyl)piperidine-l- carboxylate
Figure imgf000100_0001
[0233] A mixture of 2-cyanoacetic acid (226 mg, 2.66 mmol), (A)-l-boc-3- (aminomethyl)piperidine (570 mg, 2.66 mmol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1; 663 mg, 3.46 mmol), hydroxybenzotriazole hydrate (HOBt.TLO; 529 mg, 3.46 mmol), triethylamine (EtiN; 1.11 mL, 7.98 mmol), and dichloromethane (13.3 mL) was stirred at room temperature for 18 hours to produce tert-butyl (R)-3-((2-cyanoacetamido)methyl)piperidine-l-carboxylate. The product was purified by medium -pressure liquid chromatography (MPLC) on silica (0-100% ethyl acetate (EtOAc)/Hexanes) as a colorless oil (693 mg, 2.46 mmol, 93%). Rf = 0.62 (100% EtOAc).
Example III-2: Synthesis of (R)-N-((l-(5-chloro-2-methoxybenzoyl)piperidin-3- yl)methyl)-2-cyanoacetamide
Figure imgf000100_0002
[0234] To a mixture of tert- butyl (A)-3-((2-cyanoacetamido)methyl)piperidine-l- carboxylate (2.4 g, 8.53 mmol) in dichloromethane (DCM; 33 mL) at 0 °C was added trifluoroacetic acid (TFA; 6.52 mL, 85.3 mmol). The reaction was stirred at 0 °C for 10 minutes, then warmed to room temperature (RT) and stirred for a further 1 hour, at which point no starting material remained (confirmed by thin layer chromatography, TLC). The solvent was removed in vacuo and the residue was redissolved in DCM (43 mL). 5-Chloro-2- methoxybenzoic acid (1.59 g, 8.53 mmol) was added followed by 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 3.57 g, 9.38 mmol) and triethylamine (EtoN; 3.57 mL, 25.6 mmol) and the reaction was allowed to stir at RT for 18 h. The resulting mixture was transferred to a separatory funnel and washed sequentially with water (40 mL) and brine (40 mL). The organic layer were separated then dried over sodium sulfate (NaiSCri), and the solvent was removed in vacuo. The residue was purified by MPLC on silica (0-100%
EtO Ac/Hexanes) to give (R)-N-((l-(5-chloro-2-methoxybenzoyl)piperidin-3-yl)methyl)-2- cyanoacetamide as a white crystalline solid (1.91 g, 5.46 mmol, 64%).
Example III-3: Synthesis of (R,E)-N-((l-(5-chloro-2-methoxybenzoyl)piperidin-3- yl)methyl)-2-cyano-3-(4-methoxyphenyl)acrylamide
Figure imgf000101_0001
[0235] To a flask containing 4-methoxybenzaldehyde (7.16 xlO 2 mmol, 1 equiv.) was added (i?)-N-((l-(5-chloro-2-methoxybenzoyl)piperidin-3-yl)methyl)-2-cyanoacetamide (25 mg, 7.16 xlO 2 mmol, 1 equiv.) in dimethylsulfoxide (DMSO; 716 uL). Piperidine (2.1 uL, 2.15 x 10 2 mmol, 0.3 equiv.) was added and the reaction mixture was heated to 100 °C for 18 hours. The resulting mixture was fdtered, then purified by Cl 8 RP preparative high performance liquid chromatography (HPLC; 15-100% methanol/TkO (0.05 % HCOOH)) to obtain (R,E)-N-((l-(5-chloro-2-methoxybenzoyl)piperidin-3-yl)methyl)-2-cyano-3-(4- methoxy pheny l)acry 1 ami de .
[0236] Compounds synthesized using methods similar to those described in the above Examples are provided in Table III- 1. able III-l. Synthesized compounds
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Table III-2. Characterization of Synthesized Compounds
Figure imgf000104_0002
Example III-4: Covalent modification analysis using Matrix Assisted Laser
Desorption/Ionization - Time of Flight Mass Spectrometry (MALDI-TOF MS)
[0237] Compounds of the synthesized library are evaluated for covalent modification of K- Ras4b 1-188 protein using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), to confirm covalent labeling at Cl 85.
[0238] Reaction: 20 mM of K-Ras4b (1-188) protein (Protein Expression Laboratory, FNLCR/Leidos Biomed.) in 20 mM HEPES buffer containing 150 mM NaCl, 1 mM MgCb, pH 7.3 is prepared freshly before assay. 20 mΐ aliquots of protein are dispensed in a 384-well polypropylene plate, then compounds to be tested (0.8 pi, 10 mM in DMSO) are added to different wells. For each assay, three blank and three control samples are prepared by mixing 20 mΐ of protein solution with 0.8 mΐ DMSO or 10 mM standard compound. The contents of the wells are 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.
[0239] Target plate pretreatment: Before each assay, the MALDI target plate (Bruker MTP 384 ground steel BC) is 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.
[0240] Sample preparation: After the 24 h reaction described above, 2 mΐ of the reaction mixture is 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 is mixed by aspiration, centrifuged at 2000 g for 1 minute, then 2 mΐ aliquots are 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 is dried under mild vacuum to produce spots with fine crystalline structure.
[0241] Measurements: MALDI-TOF measurements are performed on a Bruker Daltonics ultraflex III TOF-TOF mass spectrometer using linear mode and mass range from 5 to 45 kDa. Detector gain is set to 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 are automatically collected using a custom AutoXecute method. Laser power is auto-adjusted using fuzzy control. The peak selection range is set to be between 20500 and 23000 Da. Peak evaluation uses half width parameter set to be smaller than 30 Da. Fuzzy control uses Proteins/Oligonucleotides protocol with minimum half width 1/6 times above threshold. Up to 1500 shots are collected in 500 shot steps. Dynamic termination is implemented to finish data collection when peak intensity is reaching value of 1200 [a.u.].
[0242] Spectra processing: Spectra are smoothed by SavitzkyGolay algorithm using 12 m/z width and six cycles. Centroid peak detection algorithm is used with signal to noise threshold set to 11, relative intensity threshold 5%, minimum intensity threshold 50 [a.u.], peak width 20 m/z and TopHat baseline subtraction. Peak intensity and area under the peak are evaluated and recorded for all peaks between 21,460 Da and 23,500 Da.
Example III-5: Cell proliferation assays
[0243] Compounds of the synthesized library are also evaluated using cell-based screens using a mouse embryonic fibroblast (MEF) cell line panel containing single RAS transgene alleles. These MEFs are endogenous HRAS, NRAS and KRAS null, and their growth is dependent on exogenous RAS or activated MARK pathway genes. By adding back specific isoforms of RAS genes or other pathway activators, cell lines can be developed which are dependent on these genes, but are still close to an isogenic background. The MEF panel includes oncogenic mutants of KRAS4b as well as wild type alleles of the other RAS isoforms (e.g. K-Ras4b G12D, K-Ras4b G12V, K-Ras4b Q61R, H-Ras WT). The control cell line is KRAS G12D MEF that carries C185S mutation (preventing posttranslational modification by farnesyl), and membrane attachment that is necessary for K-Ras signaling is enabled through N-terminal myristoyl moiety (Myr-K-Ras G12D/C185S). Cell viability in the presence of synthesized compounds is measured using CellTiter-Glo® (Promega).
[0244] Cells are plated in black-walled 384-well plates (Greiner, 781091) at densities in accordance with their doubling time (for MEFs typically 1,000 cells/well in 20 mΐ), using the Multidrop Combi Reagent Dispenser (Thermo). They are then incubated overnight at 37 °C in a humidified atmosphere of 5% CO2 prior to drug addition. Compound and DMSO addition to microplates is performed using the Access™ Laboratory Workstation (Labcyte®) and Echo 555 (Labcyte®) liquid handler. Source plates with compounds and DMSO are prepared, and the Echo 555 is used to transfer 50 nL of compound, DMSO, or combination to the appropriate wells. Five pL of complete culture medium is added to all wells of the microplate after compound addition. The highest final compound concentration in each assay is 100 mM or 50 mM with between seven to 12 dilutions. The final DMSO concentration in all wells is 0.2%.
[0245] Cells are incubated with compounds for 72h. All conditions are done in triplicate and experiments performed at least thrice. Cellular ATP levels (an indicator of cell count) are determined with the CellTiter-Glo (CTG, Promega G7573) luminescence assay, using an EnVision Plate Reader (PerkinElmer).
[0246] Plates are harvested at two time points. At the time of drug addition, one plate for each cell line with no compounds added receives 5 pL of media and are harvested to represent a measurement of the cell population at the time of compound addition (TO). After 72 h incubation, the compound-treated plates are harvested using CTG reagent and the luminescence is read using the EnVision giving control growth (C) and compound treated well (T72) measurements. Growth inhibition is calculated by:
T72 - TO
——— X 100
C - TO
[0247] Dose-response curves are generated using Prism 7 software (GraphPad).
Example III-6: Immunoblot analysis
[0248] Certain compounds of the synthesized library are evaluated for effect on localization of KRAS in cell membranes.
[0249] Cells (MEF K-Ras Q61R, K-Ras G12D, and Myr-K-Ras G12D/C185S) are rinsed thrice with ice-cold PBS and then are lysed on ice with ice-cold TNE buffer supplemented with Halt protease and phosphatase inhibitors (Thermo Scientific). This is then centrifuged at 15,000g for 15 minutes to collect whole-cell lysates. Protein concentration is measured with the BCA protein assay (Pierce). Thirty micrograms of total protein per sample is loaded into 4%-l2% NuPAGE Bis-Tris gradient gels (Life Technologies) and separated by SDS-PAGE. Proteins are transferred to polyvinylidene difluoride (PVDF) membranes. The following antibodies are used for immunoblotting: mouse monoclonal anti-K-Ras (Sigma
WH0003845M1, clone 3B10-2F2), mouse anti-Ras (Thermo 1862335), rabbit anti-pERKl/2 (T202/Y204; Cell Signaling Technology 4370), mouse anti-ERKl/2 (Cell Signaling
Technlogy 4696), rabbit anti-p-MEKl/2 (S217/221; Cell Signaling Technology 9154), mouse anti-MEKl/2 (Cell Signaling Technology 4694), rabbit anti-p-AKT (S473; Cell Signaling Technology 4060), mouse anti-AKT (Cell Signaling Technology 2920). Vinculin (rabbit anti-vinculin, Cell Signaling Technology 4650) is used as a loading control. Primary antibodies are detected with fluorescence-conjugated (LI-COR) secondary antibodies.
[0250] For cell fractionation experiments, cells (MEF K-Ras G12D, K-Ras G12V, and K- Ras WT) 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-K-Ras (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 III-7: Tumor Xenograft
[0251] 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 10s 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. [0252] 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.

Claims

What is claimed is:
1. A compound of F ormul a (III) :
Figure imgf000110_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is 4- to 8-membered heterocycloalkyl;
B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2- -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2-;
each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
RC5° js 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;
Rcl is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRc8Rc9, -ORcl°, and S02Rc11, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -S02Rc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halo;
each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, halocycloalkyl, heterocycloalkyl, or haloheterocycloalkyl;
or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc2 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rc3 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more halo;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl, unsubstituted or substituted with one or more halo;
or Rc2 and Rc3, 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 Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRC52Rc53, -NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16;
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, -ORc17, =0, - RC18Rc19, -CN, -SFs, -S02NRc54Rc55, -SRc56,
-SC>2Rc57, and Rc23, wherein each Rc23 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, -ORc20, =0, -NRc21Rc22, -CN, -SFS, -S02NRC58Rc59, -SRc60,
-SC>2Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Gcich Rcl2 Rcl 3 J^cl4 Jjcl5 Rc3^ Rc 32 Rc 3^ Rc3^ J^c20 j^c21 J^c22 j^c52 j^c53
Rc54, Rc55, Rc56, Rc57, Rc58, Rc59, Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, or haloalkynyl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl\ Rcl4, Rcl7, Rcl8, Rcl9, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rc62 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, -NRC24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NFh, -SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl; and each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, -CN, -SFs, -NO2, =0, -ORc27, and -NRc28Rc29; wherein each alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, -O- alkyl, -OH, -O-haloalkyl, =0, -CN, -NIL·, and -SFs;
and each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl; m is an integer from 0 to 13;
n is an integer from 0 to 11; and
v is an integer from 0 to 11
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;
Z is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl,
wherein when A is piperidinyl and B is phenyl or thiophenyl, Z is hydrogen, alkyl, cycloalkyl, aryl, 6- to lO-membered heteroaryl, 5-membered heteroaryl comprising two or more annular N atoms, or 5-membered heteroaryl comprising at least one annular O or S atom;
X is -S(O)-, -S(0)2- -S(0)NRc50-, -C(S)-, -C(O)-, or -C(Rc7)2- each Rc7 is independently hydrogen, halo, alkyl, or haloalkyl;
Rc50 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;
Rcl is hydrogen, alkyl, or cycloalkyl;
Rc2 and Rc3 are independently selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, -NO2, -CN, -SO2NH2, -NRc8Rc9, -ORcl°, and -S02RcU, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each Rc4 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2NH2, -NRC8Rc9, -ORc1°, =0, -SRc51, and -SC>2Rc11, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is independently unsubstituted or substituted with one or more halo;
each Rc8, Rc9, Rcl°, Rcl1, and Rc51 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, or halocycloalkyl;
or two to four Rc4, together with the atoms to which they are attached, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
or Rc2 and one Rc4, together with the atoms to which they are attached, form a
cycloalkyl or heterocycloalkyl;
or Rcl and one Rc4, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rcl and Rc2, together with the atoms to which they are attached, form a
heterocycloalkyl;
or Rc2 and Rc3, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl;
each Rc5 is independently selected from the group consisting of halo, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, -NO2, -CN,
-S02NRC52Rc53, -NRC12Rc13, -ORc14, -S02Rc15, =0, and -SRc16,
wherein each cycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, ORc17, =0, NRcl8Rc19, CN, SFs, S02NRc54Rc55, SRc56, -S02Rc57, and Rc23, wherein each Rc23 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 Rc23, wherein each Rc23 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, -ORc20, =0, -NRC21Rc22, -CN, -SFs, -S02NRC58Rc59, -SRc60,
-S02Rc61, and Rc62, wherein each Rc62 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
63.ch Rcl5 Rcl6 Rcl7 J^cl8 cl9 j^c52 j^c53 j^c54 j^c55 j^c56 j^c57 J^c58 j^c59
Rc60, and Rc61 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl;
each Rcl2, Rcl3, Rc20, Rc21, and Rc22 is independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, or aryl;
each Rcl4 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkynyl;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl of Rcl2, Rcl3, Rcl4, Rc20, Rc21, Rc22, and Rc23, and each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of Rc62 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,
-NRC24Rc25, -ORc26, and -SFs;
wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, alkynyl, halo, -CN, -SFs, =0, -NRc40Rc41, -NRC42C(0)Rc43, -ORc44, and Rc63, wherein each Rc63 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein each Rc63 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of =0, -NFb, SFs, -OH, -O-alkyl, -O-haloalkyl, halo, alkyl, and haloalkyl;
each Rc24, Rc25, Rc26, Rc40, Rc41, Rc42, Rc43, and Rc44 is independently hydrogen, alkyl, or haloalkyl;
each Rc6 is independently selected from the group consisting of halo, alkyl, haloalkyl,
-ORc27, and -NRc28Rc29, wherein each Rc27, Rc28, and Rc29 is independently hydrogen, alkyl, or haloalkyl;
m is an integer from 0 to 13;
n is an integer from 0 to 11; and v is an integer from 0 to 11.
3. The compound of claim 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is aryl or heteroaryl.
4. The compound of any one of claims 1 to 3, wherein the compound is of Formula (III-
A):
Figure imgf000116_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7; and
B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
5. The compound of any one of claims 1 to 4, wherein the compound is of Formula (III- A-ii):
Figure imgf000116_0002
-ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
B, X, Rc4, Rc5, RcS, and n are as defined for Formula (III).
6. The compound of any one of claims 1 to 3, wherein the compound is of Formula (III- B):
Figure imgf000117_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(RC49)2- -S(0)r- -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2; and
B, Z, X, Rc4, Rc5, Rc6, n, and v are as defined for Formula (III).
7. The compound of any one of claims 1 to 3, or 6, wherein the compound is of Formula (III-B-ii):
Figure imgf000117_0002
ii), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(Rc49)2-, -S(0)r- -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4 ;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
B, X, Rc4, Rc5, Rc6, and n are as defined for Formula (III).
8. The compound of claim 6 or 7, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is -CFh-
9. The compound of any one of claims 1 to 3, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is 5- or 6-membered heterocycloalkyl.
10. The compound of any one of claims 1 to 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered heterocycloalkyl or 5- or 6- membered heteroaryl, wherein the heterocycloalkyl or heteroaryl comprises one to three ring heteroatoms independently selected from the group consisting of O, N, and S.
11. The compound of any one of claims 1 to 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein 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.
12. The compound of any one of claims 1 to 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C9-Cio)bicyclic aryl.
13. The compound of any one of claims 1 to 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is a (C5-Cio)cycloalkyl.
14. The compound of any one of claims 1 to 13, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one or more Rc5 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; and (Ci-C4)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, -NRc21Rc22, and -CN.
15. The compound of any one of claims 1 to 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein B is phenyl and n is an integer from 0 to 5.
16. The compound of any one of claims 1 to 4, 6, or 9 to 15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 5-membered heteroaryl.
17. The compound of claim 16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is pyrazolyl, thiophenyl, furanyl, or oxazolyl.
18. The compound of any one of claims 1 to 4, 6, or 8 to 15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 9-membered heteroaryl.
19. The compound of claim 18, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is benzothiophenyl or indolyl.
20. The compound of any one of claims 1 to 4, 6, or 8 to 15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is a 6-membered heteroaryl.
21. The compound of any one of claims 1, 2, 4, 6, or 8 to 15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z is alkyl or cycloalkyl.
22. The compound of any one of claims 1 to 5, 9, or 14, wherein the compound is of Formula (III-A-i):
Figure imgf000119_0001
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
23. The compound of claim 1 to 3, 6 to 9, or 14, wherein the compound is of Formula
(III-B-i):
Figure imgf000119_0002
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7; Y is -C(RC49)2-,— S(0)— , -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4;
r is 0, 1, or 2;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
24. The compound of any one of claims 1 to 5, 9, or 14, wherein the compound is of Formula (III-A-iii):
Figure imgf000120_0001
-iii)
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
25. The compound of claim 1 to 3, 6 to 9, or 14, wherein the compound is of Formula (III-B-iii):
Figure imgf000120_0002
iii)
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
p is an integer from 0 to 7;
Y is -C(Rc49)2- -SIC)),- -0-, or -N(Rc49)-, wherein each Rc49 is independently hydrogen or Rc4; r is 0, 1, or 2;
d is an integer from 0 to 5; and
X, Rc4, Rc5, and Rc6 are as defined for Formula (III).
26. The compound of any one of claims 1 to 25, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rc5 is:
Figure imgf000121_0001
wherein:
Rc30 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, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, =0, -ORc33, -SFs, and -NRc34Rc35;
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, -ORc36,
-NRC45Rc46, -NRC47C(0)Rc48, 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 -SF5;
each Rc31 and Rc32 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, -ORc37, and
-NRc38Rc39;
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 Rc31 and one Rc32 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 Rc33, Rc34, Rc35, Rc36, Rc37, Rc38, Rc39, Rc45, Rc46, Rc47, and Rc48 is independently hydrogen, alkyl, or haloalkyl;
and q is 1 or 2.
27. The compound of claim 26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is 1 and Rc31 is hydrogen.
28. The compound of any one of claims 1 to 27, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rc5 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 Rc23.
29. The compound of claim 28, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Rc23 is alkyl substituted with aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with haloalkyl or -SFs.
30. The compound of any one of claims 1 to 29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -S(0)2-
31. The compound of any one of claims 1 to 29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -C(O)-.
32. The compound of any one of claims 1 to 29, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CH2-.
33. The compound of any one of claims 1 to 21 or 26 to 32, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
34. The compound of any one of claims 1 to 3, 9 to 21, or 26 to 32, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
35. The compound of any one of claims 4 to 8, or 22 to 25, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.
36. The compound of any one of claims 1 to 35, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein at least one Rc6 is chloro, fluoro, methoxy, methyl, -OH, -CF3, or -N(CH3)2.
37. The compound of claim 1, wherein the compound is:
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000124_0002
stereoisomer or pharmaceutically acceptable salt of any of the foregoing.
38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
39. A method of reducing the level of a K-Ras protein in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
40. The method of claim 39, wherein the K-Ras protein is human K-Ras4b.
41. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 37, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
42. The method of claim 41, wherein the disorder is cancer.
43. The method of claim 42, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
44. The method of claim 41, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
45. The method of any one of claims 41 to 44, wherein the disorder is associated with a mutation of K-Ras.
46. Use of a compound of any one of claims 1 to 37, or a stereoisomer or
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the level of a K-Ras protein in a subject in need thereof.
47. The use of claim 46, wherein the K-Ras protein is human K-Ras4b.
48. Use of a compound of any one of claims 1 to 37, or a stereoisomer or
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
49. The use of claim 48, wherein the disorder is cancer.
50. The use of claim 49, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
51. The use of claim 48, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
52. The use of any one of claims 48 to 51, wherein the cancer is associated with a mutation of K-Ras.
53. A compound according to any one of claims 1 to 37, or a stereoisomer or
pharmaceutically acceptable salt thereof, for use in a method of reducing the level of a K-Ras protein in a subject in need thereof.
54. The compound for use of claim 53, wherein the K-Ras protein is human K-Ras4b.
55. A compound according to any one of claims 1 to 37, or a stereoisomer or
pharmaceutically acceptable salt thereof, for use in a method of treating a disorder in a subject in need thereof.
56. The compound for use of claim 55, wherein the disorder is cancer.
57. The compound for use of claim 56, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.
58. The compound for use of claim 55, wherein the disorder is neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, or Legius syndrome.
59. The compound for use of any one of claims 55 to 58, wherein the cancer is associated with a mutation of K-Ras.
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