US2017114323A1PendingUtilityA1
Uses of kinase inhibitors for inducing and maintaining pluripotency
Assignee: WHITEHEAD INST BIOMEDICAL RESPriority: Jun 19, 2014Filed: Jun 19, 2015Published: Apr 27, 2017
Est. expiryJun 19, 2034(~7.9 yrs left)· nominal 20-yr term from priority
C12N 2501/11C12N 5/0606C12N 2501/999C12N 2501/727C12N 2501/115C12N 2501/165C12N 5/0696
45
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Claims
Abstract
The present disclosure provides compounds of any one of Formulae (A) to (L). The present disclosure also provides compositions, uses, and methods that include or involve a compound described herein, a serine/threonine-protein kinase B-Raf (BRAF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor 1 (VEGFR1) inhibitor, a fibroblast growth factor receptor 1 (FGFR1) inhibitor, or a combination thereof. The compounds, compositions, uses, and methods are useful in changing the pluripotency state of a vertebrate cell to a more naive state.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for changing the pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a serine/threonine-protein kinase B-Raf (BRAF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor 1 (VEGFR1) inhibitor, or a fibroblast growth factor receptor 1 (FGFR1) inhibitor; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of culturing step.
2 . The method of claim 1 , wherein the cell is cultured and maintained in the presence of a mitogen-activated protein kinase kinase (MEK) inhibitor.
3 . The method of claims 1 or 2 , wherein the cell is cultured and maintained in the presence of a glycogen synthase kinase 3 (GSK3) inhibitor, a rho-associated protein kinase (ROCK) inhibitor, and/or a proto-oncogene tyrosine-protein kinase (Src) inhibitor.
4 . The method of any one of claims 1 - 3 , wherein the cell is cultured and maintained in the presence of a BRAF inhibitor, a MEK inhibitor, and a GSK3 inhibitor.
5 . The method of any one of claims 1 - 3 , wherein the cell is cultured and maintained in the presence of a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, and a ROCK inhibitor.
6 . The method of any one of claims 1 - 3 , wherein the cell is cultured and maintained in the presence of a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, a ROCK inhibitor, and an Src inhibitor.
7 . The method any one of claims 1 - 3 , wherein the cell is cultured and maintained in the presence of a BRAF inhibitor, a MEK inhibitor, a ROCK inhibitor, and an Src inhibitor.
8 . A method for changing the pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (A):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of culturing step;
wherein:
L A1 is a substituted or unsubstituted, saturated or unsaturated, C 1-4 aliphatic chain, optionally wherein one, two, or three chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR A5 —, —N═, or ═N—, wherein each instance of R A5 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
L A2 is a substituted or unsubstituted, saturated or unsaturated, C 1-6 aliphatic chain, optionally wherein one, two, or three chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR A6 —, —N═, or ═N—, wherein each instance of R A6 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R A1 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R A2 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
n2 is 0, 1, 2, 3, 4, 5, 6, or 7;
each instance of R A3 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
n3 is 0, 1, 2, or 3;
each instance of R A4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
n4 is 0, 1, 2, 3, or 4.
9 . The method of claim 8 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
10 . The method of claim 8 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
11 . The method of claim 8 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
12 . The method of any one of any one of claims 8 - 11 , wherein R A1 is hydrogen.
13 . The method of any one of claims 8 - 12 , wherein at least one instance of R A2 is substituted or unsubstituted alkyl.
14 . The method of any one of claims 8 - 13 , wherein n3 is 0.
15 . The method of any one of claims 8 - 14 , wherein n4 is 0.
16 . The method of any one of claims 8 - 15 , wherein at least one instance of R A5 is hydrogen.
17 . The method of any one of claims 8 - 16 , wherein at least one instance of R A6 is hydrogen.
18 . The method of claim 8 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
19 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (B):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
L B1 is —N(R B4 )C(═O)—, —C(═O)N(R B4 )—, or —N(R B4 )C(═O)N(R B4 )—, wherein each instance of R B4 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
when L B1 is —N(R B4 )C(═O)— or —C(═O)N(R B4 )—, L B1 is directly attached to the carbon atom labeled with 3 or 5;
when L B1 is —N(R B4 )C(═O)N(R B4 )—, L B1 is directly attached to the carbon atom labeled with 4;
L B2 is —O—, —S—, —NR B5 —, or —C(R B6 ) 2 —, wherein R B5 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group; and each instance of R B6 is independently hydrogen, halogen, or substituted or unsubstituted alkyl;
each of X B1 , X B2 , and X B3 is independently N or CR B7 , wherein each instance of R B7 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R B1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
o1 is 0, 1, 2, 3, 4, or 5;
each instance of R B2 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
o2 is 0, 1, 2, 3, or 4;
each instance of R B3 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 , or an instance of R B3 and an instance of R B7 are joined to form a substituted or unsubstituted heterocyclic ring; and
o3 is 0, 1, or 2.
20 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
21 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
22 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
23 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein each of R B9 and R B10 is independently substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
24 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
25 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein Ring B is a substituted or unsubstituted, monocyclic, 5- to 6-membed heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur.
26 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
27 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
28 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
29 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
30 . The method of any one of claims 19 - 29 , wherein at least one instance of R B1 is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted, monocyclic, 5- to 6-membed heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
31 . The method of any one of claims 19 - 30 , wherein at least one instance of R B2 is halogen or substituted or unsubstituted alkyl.
32 . The method of any one of claims 19 - 31 , wherein o2 is 0.
33 . The method of any one of claims 19 - 32 , wherein at least one instance of R B3 is substituted or unsubstituted heteroaryl or —C(═O)N(R a ) 2 , or an instance of R B3 and an instance of R B7 are joined to form a substituted or unsubstituted, monocyclic, 5- to 6-membed heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur.
34 . The method of any one of claims 19 - 33 , wherein each instance of R B4 is hydrogen.
35 . The method of any one of claims 19 - 34 , wherein R B5 is hydrogen.
36 . The method of claim 19 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
37 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (C):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
Ring C1 is a substituted or unsubstituted, monocyclic, 5- to 6-membered heterocyclic ring or a substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl ring, wherein one or two atoms in the heterocyclic or heteroaryl ring system are nitrogen;
Ring C2 is a substituted or unsubstituted, monocyclic, 6-membered carbocyclic ring or a substituted or unsubstituted phenyl ring;
Ring C3 is a substituted or unsubstituted, monocyclic, 5- to 6-membered heterocyclic ring or a substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl ring, wherein one or two atoms in the heterocyclic or heteroaryl ring system are nitrogen;
each instance of R C1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
p1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
each instance of R C2 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 , or two instances of R C2 are joined to form a substituted or unsubstituted carbocyclic ring;
p2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;
each instance of R C3 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
p3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
38 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
39 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein Ring C4 is a substituted or unsubstituted, monocyclic, 5- to 6-membed carbocyclic ring.
40 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
41 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
42 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
43 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein Ring C5 is a substituted or unsubstituted, monocyclic, 5- to 6-membed carbocyclic ring.
44 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
45 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
46 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
47 . The method of any one of claims 37 - 46 , wherein at least one instance of R C1 is substituted or unsubstituted alkyl, —OR a , —N(R a ) 2 , or —CN.
48 . The method of any one of claims 37 - 47 , wherein at least one instance of R C2 is halogen or —OR a .
49 . The method of any one of claims 37 - 48 , wherein at least one instance of R C3 is substituted or unsubstituted alkyl.
50 . The method of any one of claims 37 - 49 , wherein p3 is 0.
51 . The method of claim 37 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
52 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (D):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
L D1 is a substituted or unsubstituted, saturated or unsaturated, C 3-7 aliphatic chain, optionally wherein one, two, or three chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR D6 —, —N═, or ═N—, wherein each instance of R D6 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R D1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
q1 is 0, 1, 2, 3, 4, or 5;
each instance of R D2 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R D3 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
q3 is 0, 1, 2, or 3;
each instance of R D4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
q4 is 0, 1, 2, or 3; and
each instance of R D5 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
53 . The method of claim 52 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein R D7 is substituted or unsubstituted phenyl.
54 . The method of any one of claims 52 - 53 , wherein L D1 is a substituted or unsubstituted, saturated or unsaturated, C 5 aliphatic chain, optionally wherein one, two, or three chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR D6 —, ═N—, or —N═.
55 . The method of any one of claims 52 - 54 , wherein at least one instance of R D1 is halogen.
56 . The method of any one of claims 52 - 55 , wherein each instance of R D2 is hydrogen.
57 . The method of any one of claims 52 - 56 , wherein q3 is 0.
58 . The method of any one of claims 52 - 57 , wherein q4 is 0.
59 . The method of any one of claims 52 - 58 , wherein each instance of R D5 is hydrogen.
60 . The method of any one of claims 52 - 59 , wherein at least one instance of R D6 is hydrogen.
61 . The method of claim 52 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
62 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (E):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of culturing step;
wherein:
X E1 is —O—, —S—, —C(═O)—, —C(═S)—, or —C(═NR E4 )—, wherein R E is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
X E2 is —O—, —S—, —C(═O)—, or —C(—S)—;
R E1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 , or R E1 and R E are joined to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R E2 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
r2 is 0, 1, 2, or 3;
each instance of R E3 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
r3 is 0, 1, 2, 3, or 4.
63 . The method of claim 62 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
64 . The method of any one of claims 62 - 63 , wherein R E1 is substituted or unsubstituted, monocyclic, 5- to 6-membered heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur.
65 . The method of claim 62 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
each instance of R E5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
r5 is 0, 1, 2, or 3.
66 . The method of claim 62 , wherein the compound is of the formula:
67 . The method of any one of claims 65 - 66 , wherein at least one instance of R E5 is substituted or unsubstituted, monocyclic, 5- to 6-membed heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur.
68 . The method of claim 62 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein X E3 is C or N, and Ring E is a substituted or unsubstituted, monocyclic, 5- to 6-membered heterocyclic ring or a substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl ring, wherein one, two, or three atoms in the heterocyclic or heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
69 . The method of claim 62 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein R E6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
70 . The method of claim 69 , wherein R E6 is hydrogen.
71 . The method of any one of claims 62 - 70 , wherein r2 is 0.
72 . The method of any one of claims 62 - 71 , wherein r3 is 0.
73 . The method of claim 62 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
74 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (F):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
X F is —N(R F9 )—, ═N—, —C(R F10 ) 2 —, or ═C(RF 10 )—, wherein:
R F9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; and
each instance of R F10 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R F1 is absent, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
R F2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
R F3 is absent, hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl, or R F3 and R F2 are joined to form ═O;
R F4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
R F5 is absent, hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
R F6 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
R F7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; and
R F8 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
75 . The method of claim 74 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
76 . The method of claim 74 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
77 . The method of claim 74 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
78 . The method of any one of claims 74 - 77 , wherein R F1 is absent, substituted or unsubstituted alky, or substituted or unsubstituted, monocyclic, 5- to 6-membed carbocyclyl.
79 . The method of any one of claims 74 - 78 , wherein R F2 is —NR a C(═O)N(R a ) 2 .
80 . The method of any one of claims 74 - 78 , wherein R F2 and R F3 are joined to form ═O.
81 . The method of any one of claims 74 - 80 , wherein R F4 is hydrogen or substituted or unsubstituted alkyl.
82 . The method of any one of claims 74 - 81 , wherein R F5 is absent or hydrogen.
83 . The method of any one of claims 74 - 82 , wherein R F6 is hydrogen.
84 . The method of any one of claims 74 - 83 , wherein R F7 is substituted or unsubstituted alkyl or substituted or unsubstituted, monocyclic, 5- to 6-membed heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
85 . The method of any one of claims 74 - 84 , wherein R F8 is hydrogen.
86 . The method of any one of claims 74 - 85 , wherein R F9 is substituted or unsubstituted phenyl.
87 . The method of any one of claims 74 - 86 , wherein at least one instance of R F10 is substituted or unsubstituted phenyl, or —C(═O)R a .
88 . The method of claim 74 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
89 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (G):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of culturing step;
wherein:
Ring G is a substituted or unsubstituted phenyl ring or a substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl ring, wherein one or two atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur;
each instance of R G1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
t1 is 0, 1, 2, 3, 4, or 5;
L G is a bond, —O—, —S—, —N(R G5 )—, or —C(R G6 ) 2 —, wherein R G5 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group; and each instance of R G6 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
R G2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R G3 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R G4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —S(═O) 2 R a , —S(═O) 2 OR a , or —S(═O) 2 N(R a ) 2 ; and
t4 is 0, 1, 2, 3, or 4.
90 . The method of claim 89 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
91 . The method of claim 89 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
92 . The method of claim 89 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
93 . The method of any one of claims 89 - 92 , wherein at least one instance of R G1 is substituted or unsubstituted alkyl, —C(═O)N(R a ) 2 , or —N(R a )C(═O)R a .
94 . The method of any one of claims 89 - 93 , wherein R G2 is substituted or unsubstituted phenyl.
95 . The method of any one of claims 89 - 94 , wherein R G3 is hydrogen.
96 . The method of any one of claims 89 - 95 , wherein at least one instance of R G4 is halogen, —C(═O)OR a , —S(═O) 2 R a , or —S(═O) 2 N(R a ) 2 .
97 . The method of any one of claims 89 - 96 , wherein R G5 is hydrogen.
98 . The method of claim 89 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
99 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (H):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
L H is a substituted or unsubstituted, saturated or unsaturated, C 1-4 aliphatic chain, optionally wherein one or two chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR H5 —, —N═, or ═N—, wherein each instance of R H5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
each instance of R H1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
u1 is 0, 1, 2, 3, 4, or 5;
R H2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R H3 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
u3 is 0, 1, or 2;
each instance of R H4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
u4 is 0, 1, 2, 3, 4, or 5.
100 . The method of claim 99 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
101 . The method of claim 99 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
102 . The method of claim 99 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
103 . The method of any one of claims 99 - 102 , wherein at least one instance of R H1 is substituted or unsubstituted alkyl or substituted or unsubstituted, monocyclic, 5- to 6-membed heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur.
104 . The method of any one of claims 99 - 103 , wherein R H2 is hydrogen.
105 . The method of any one of claims 99 - 104 , wherein at least one instance of R H3 is halogen.
106 . The method of any one of claims 99 - 105 , wherein u3 is 0.
107 . The method of any one of claims 99 - 106 , wherein at least one instance of R H4 is substituted or unsubstituted alkyl, or —C(═O)N(R a ) 2 .
108 . The method of any one of claims 99 - 107 , wherein at least one instance of R H5 is hydrogen or substituted or unsubstituted phenyl.
109 . The method of claim 99 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
110 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
R I1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R I2 is hydrogen or substituted or unsubstituted alkyl;
R I5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted carbocyclyl;
R I6 is hydrogen or substituted or unsubstituted alkyl;
each instance of R I7 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —O-(substituted or unsubstituted alkyl), —NH-(substituted or unsubstituted alkyl), —NH-(substituted or unsubstituted aryl), —N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —N(substituted or unsubstituted alkyl)-(substituted or unsubstituted aryl), —NO 2 , or —CN; and
v7 is 0, 1, 2, 3, or 4.
111 . The method of claim 110 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
each instance of R I8 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
v8 is 0, 1, 2, 3, 4, or 5.
112 . The method of claim 111 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
113 . The method of any one of claims 110 - 112 , wherein R I2 is substituted or unsubstituted alkyl.
114 . The method of any one of claims 110 - 113 , wherein R I5 is substituted or unsubstituted alkyl.
115 . The method of any one of claims 110 - 114 , wherein R I6 is hydrogen.
116 . The method of any one of claims 110 - 115 , wherein v7 is 0.
117 . The method of any one of claims 111 - 116 , wherein v8 is 0.
118 . The method of any one of claims 111 - 117 , wherein R a is substituted or unsubstituted C 1-6 alkyl.
119 . The method of claim 110 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
120 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (J):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
L J is a substituted or unsubstituted, saturated or unsaturated, C 1-6 aliphatic chain, optionally wherein one or two chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR J6 —, —N═, or ═N—, wherein each instance of R J6 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R J1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
w1 is 0, 1, 2, 3, or 4;
R J2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R J3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
R J4 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R J5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
w5 is 0, 1, 2, 3, 4, or 5.
121 . The method of claim 120 , wherein L J is a substituted or unsubstituted, saturated or unsaturated, C 3 aliphatic chain, optionally wherein one or two chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR J6 —, —N═, or ═N—.
122 . The method of claim 120 , wherein L J is of the formula:
wherein each instance of R J7 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl.
123 . The method of claim 120 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
124 . The method of any one of claims 120 - 123 , wherein w1 is 0.
125 . The method of any one of claims 120 - 124 , wherein R J2 is hydrogen.
126 . The method of any one of claims 120 - 125 , wherein R J3 is substituted or unsubstituted alkyl.
127 . The method of any one of claims 120 - 126 , wherein R J4 is substituted or unsubstituted alkyl.
128 . The method of any one of claims 120 - 127 , wherein at least one instance of R J5 is halogen.
129 . The method of any one of claims 120 - 128 , wherein at least one instance of R J6 is hydrogen.
130 . The method of claim 120 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
131 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (K):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
R K1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R K2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R K3 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
x3 is 0, 1, 2, 3, or 4;
R K4 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R K5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
x5 is 0, 1, 2, 3, 4, or 5.
132 . The method of claim 131 , wherein R K 1 is substituted or unsubstituted alkyl.
133 . The method of claim 131 , wherein R K1 is C 1-6 alkyl substituted with at least one —OH.
134 . The method of any one of claims 131 - 133 , wherein R K2 is hydrogen.
135 . The method of any one of claims 131 - 134 , wherein at least one instance of R K3 is halogen.
136 . The method of any one of claims 131 - 135 , wherein R K4 is hydrogen.
137 . The method of any one of claims 131 - 136 , wherein at least one instance of R K5 is halogen.
138 . The method of claim 131 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
139 . A method for converting pluripotency state of a vertebrate cell to a more naïve state, the method comprising:
culturing a pluripotent vertebrate cell in the presence of a compound of Formula (L):
or a pharmaceutically acceptable salt thereof; and
maintaining the cell in culture under conditions suitable and a time sufficient to convert the pluripotency state of the vertebrate cell to a more naïve state than the pluripotency state of the vertebrate cell of the step of culturing;
wherein:
L L is a substituted or unsubstituted, saturated or unsaturated, C 1-4 aliphatic chain, optionally wherein one or two chain atoms of the aliphatic chain are independently replaced with —O—, —S—, —NR L5 —, —N═, or ═N—, wherein each instance of R L5 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R L1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
y1 is 0, 1, 2, 3, or 4;
each instance of R L2 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
y2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
each instance of R L3 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; and
each instance of R L4 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
140 . The method of claim 139 , wherein L L is a substituted or unsubstituted, saturated or unsaturated, C 2 aliphatic chain, optionally wherein one chain atom of the aliphatic chain is replaced with —O—, —S—, —NR L —, ═N—, or —N═.
141 . The method of claim 139 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
142 . The method of claim 139 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
143 . The method of any one of claims 139 - 142 , wherein y1 is 0.
144 . The method of any one of claims 139 - 143 , wherein y2 is 0.
145 . The method of any one of claims 139 - 144 , wherein each instance of R L3 is independently hydrogen or substituted or unsubstituted alkyl.
146 . The method of any one of claims 139 - 145 , wherein each instance of R L4 is hydrogen.
147 . The method of claim 139 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
148 . The method of any one of claims 1 - 147 , wherein the culture comprises fibroblast growth factor and/or Activin A.
149 . The method of any one of claims 1 - 148 , wherein the vertebrate cell is a human stem cell.
150 . The method of claim 149 , wherein the human stem cell is a human embryonic stem cell.
151 . The method of any one of claims 1 - 148 , wherein the vertebrate cell is a human induced pluripotent cell (iPS cell).
152 . The method of any one of claims 1 - 148 , wherein the vertebrate cell is derived from a human embryonic stem cell line.
153 . The method of any one of claims 1 - 148 , wherein the vertebrate cell is derived from an embryo.
154 . The method of any one of claims 1 - 153 , wherein the more naïve pluripotent vertebrate cell of the step of maintaining uses the distal Oct4 enhancer element for OCT4 expression.
155 . The method of any one of claims 1 - 154 , wherein the more naïve pluripotent vertebrate cell of the step of maintaining has a global gene expression profile which clusters with naïve mouse ESCs as opposed to stem cell lines derived from mouse epiblast (EpiSCs) and/or less naïve human ESCs.
156 . A composition comprising naïve pluripotent vertebrate cells produced by the methods of any one of claims 1 - 155 .
157 . A naïve pluripotent vertebrate cell line produced by the methods of any one of claims 1 - 155 .
158 . A naïve pluripotent vertebrate cell, wherein the cell uses the distal Oct4 enhancer element for OCT4 expression.
159 . The naïve pluripotent vertebrate cell of claim 158 , wherein the cell is a primate cell and wherein the cell uses the endogenous distal OCT4 enhancer element for Oct4 expression.
160 . The naïve pluripotent vertebrate cell of claim 158 , wherein the cell is a human cell and wherein the cell uses the endogenous distal OCT4 enhancer element for Oct4 expression.
161 . A naïve pluripotent vertebrate cell, wherein the cell has a global gene expression profile which clusters with naïve mouse ESCs as opposed to stem cell lines derived from mouse epiblast (EpiSCs) and/or less naïve human ESCs.
162 . The naïve pluripotent vertebrate cell of claim 161 , wherein the cell is a primate cell.
163 . The naïve pluripotent vertebrate cell of claim 161 , wherein the cell is a human cell.
164 . The naïve pluripotent vertebrate cell of any one of claims 158 to 163 , wherein the cell is produced by the methods of any one of claims 1 - 155 .
165 . A kit for culturing vertebrate cells, the kit comprising:
a serine/threonine-protein kinase B-Raf (BRAF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor 1 (VEGFR1) inhibitor, or a fibroblast growth factor receptor 1 (FGFR1) inhibitor; and instructions for culturing vertebrate cells.
166 . The kit of claim 165 , wherein the kit further comprises mitogen-activated protein kinase kinase (MEK) inhibitor.
167 . The kit of claims 165 or 166 , wherein the kit further comprises a glycogen synthase kinase 3 (GSK3) inhibitor, a rho-associated protein kinase (ROCK) inhibitor, and/or a proto-oncogene tyrosine-protein kinase (Src) inhibitor.
168 . The kit of any one of claims 165 - 167 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, and a GSK3 inhibitor.
169 . The kit of any one of claims 165 - 167 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, and a ROCK inhibitor.
170 . The kit of any one of claims 165 - 167 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, a ROCK inhibitor, and an Src inhibitor.
171 . The kit of any one of claims 165 - 167 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, a ROCK inhibitor, and an Src inhibitor.
172 . The kit of any one of claims 165 - 171 , wherein the kit further comprises cell culture medium.
173 . The kit of any one of claims 165 - 172 , wherein the vertebrate cells are naïve pluripotent cells, human pluripotent cells, or naïve human pluripotent cells.
174 . A kit for preparing a cell culture medium, the kit comprising:
a serine/threonine-protein kinase B-Raf (BRAF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor 1 (VEGFR1) inhibitor, or a fibroblast growth factor receptor 1 (FGFR1) inhibitor; and instructions for preparing a cell culture medium.
175 . The kit of claim 174 , wherein the kit further comprises mitogen-activated protein kinase kinase (MEK) inhibitor.
176 . The kit of claims 174 or 175 , wherein the kit further comprises a glycogen synthase kinase 3 (GSK3) inhibitor, a rho-associated protein kinase (ROCK) inhibitor, and/or a proto-oncogene tyrosine-protein kinase (Src) inhibitor.
177 . The kit of any one of claims 174 - 176 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, and a GSK3 inhibitor.
178 . The kit of any one of claims 174 - 176 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, and a ROCK inhibitor.
179 . The kit of any one of claims 174 - 176 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, a ROCK inhibitor, and an Src inhibitor.
180 . The kit of any one of claims 174 - 176 , wherein the kit comprises a BRAF inhibitor, a MEK inhibitor, a ROCK inhibitor, and an Src inhibitor.
181 . The kit of any one of claims 174 - 180 , wherein the kit further comprises a basal medium.
182 . The kit of any one of claims 174 - 181 , wherein the basal medium is a serum-free medium.
183 . The kit of any one of claims 174 - 182 , wherein the basal medium comprises one or more supplements.
184 . The method of any one of claims 1 - 155 or the kit of any one of claims 165 - 183 , wherein the BRAF inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
185 . The method of any one of claims 1 - 155 or the kit of any one of claims 165 - 183 , wherein the VEGFR1 inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
186 . The method of any one of claims 1 - 155 or the kit of any one of claims 165 - 183 , wherein the FGFR1 inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
187 . The method of any one of claims 1 - 155 or the kit of any one of claims 165 - 183 , wherein the MEK inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
188 . The method of any one of claims 1 - 155 or the kit of any one of claims 165 - 183 , wherein the GSK3 inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
189 . The method of any one of claims 1 - 155 or the kit of any one of claims 165 - 183 , wherein the ROCK inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
190 . The method of any one of claims 1 - 155 or the kit of any one of claims 165 - 183 , wherein the Src inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
191 . A cell culture medium comprising:
a basal medium; and a serine/threonine-protein kinase B-Raf (BRAF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor 1 (VEGFR1) inhibitor, or a fibroblast growth factor receptor 1 (FGFR1) inhibitor.
192 . The cell culture medium of claim 191 , wherein the cell culture medium further comprises mitogen-activated protein kinase kinase (MEK) inhibitor.
193 . The cell culture medium of claim 191 or 192 , wherein the cell culture medium further comprises a glycogen synthase kinase 3 (GSK3) inhibitor, a rho-associated protein kinase (ROCK) inhibitor, and/or a proto-oncogene tyrosine-protein kinase (Src) inhibitor.
194 . The cell culture medium of any one of claims 191 - 193 , wherein the cell culture medium comprises a BRAF inhibitor, a MEK inhibitor, and a GSK3 inhibitor.
195 . The cell culture medium of any one of claims 191 - 193 , wherein the cell culture medium comprises a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, and a ROCK inhibitor.
196 . The cell culture medium of any one of claims 191 - 193 , wherein the cell culture medium comprises a BRAF inhibitor, a MEK inhibitor, a GSK3 inhibitor, a ROCK inhibitor, and an Src inhibitor.
197 . The cell culture medium of any one of claims 191 - 193 , wherein the cell culture medium comprises a BRAF inhibitor, a MEK inhibitor, a ROCK inhibitor, and an Src inhibitor.
198 . The cell culture medium of any one of claims 191 - 197 , wherein the basal medium is a serum-free medium.
199 . The cell culture medium of any one of claims 191 - 198 , wherein the basal medium comprises one or more supplements.Join the waitlist — get patent alerts
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