US2021315894A9PendingUtilityA9
4,6-pyrimidinylene derivatives and uses thereof
Assignee: DANA FARBER CANCER INST INCPriority: Jun 26, 2015Filed: Jun 11, 2020Published: Oct 14, 2021
Est. expiryJun 26, 2035(~8.9 yrs left)· nominal 20-yr term from priority
A61K 31/497C07D 407/04A61K 45/06A61K 31/506C07D 471/04C07D 401/14C07D 401/04C07D 403/04C07D 401/12A61P 35/02A61K 2300/00
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Claims
Abstract
The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., lung cancer, breast cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma, brain cancer, neuroblastoma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase (e.g. a protein kinase (e.g. a cyclin-dependent kinase (CDK) (e.g. CDK7, CDK12, or CDK13) or a lipid kinase such as a phosphatidylinositol-5-phosphate 4-kinase (PIP4K) (e.g., PI5P4Kα, PI5P4Kβ, or PI5P4Kγ)) in the subject.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a substituted or unsubstituted heteroaryl ring;
each instance of R A 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 ring, or substituted or unsubstituted, heteroaryl ring;
k is 0, 1, 2, 3, 4, 5, or 6;
L 1 is a bond, —C(R b ) 2 —, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —NR c —;
each instance of R b is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R c is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R B1 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 B2 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 ;
X is —C(R b ) 2 —, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR c —, —C(R b ) 2 C(R b ) 2 —, —C(R b ) 2 C(═O)—, —C(═O)C(R b ) 2 —, (E)-CR b ═CR b —, (Z)—CR b ═CR b —, —C≡C—, —OC(═O)—, —C(═O)O—, —SC(═O)—, —C(═O)S—, —NR c C(═O)—, —C(═O)NR c —, —OC(R b ) 2 —, —C(R b ) 2 O—, —SC(R b ) 2 —, —C(R b ) 2 S—, —NR c C(R b ) 2 —, —C(R b ) 2 NR c —, —S(═O)O—, —OS(═O)—, —S(═O)NR c —, —NR c S(═O)—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR c —, or —NR c S(═O) 2 —;
Ring C is a substituted or unsubstituted phenyl ring, substituted or unsubstituted, monocyclic carbocyclic ring, substituted or unsubstituted, monocyclic heterocyclic ring, or substituted or unsubstituted, monocyclic heteroaryl ring;
Ring D is a substituted or unsubstituted phenyl ring, substituted or unsubstituted, monocyclic carbocyclic ring, or substituted or unsubstituted, monocyclic heterocyclic ring;
provided that at least one of Ring C and Ring D is a substituted or unsubstituted phenyl ring;
each instance of R C 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 ;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
L 2 is —C(R b ) 2 —, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR c —, —C(R b ) 2 C(R b ) 2 —, —C(R b ) 2 C(═O)—, —C(═O)C(R b ) 2 —, (E)-CR b ═CR b —, (Z)—CR b ═CR b —, —C≡C—, —OC(═O)—, —C(═O)O—, —SC(═O)—, —C(═O)S—, —NR c C(═O)—, —C(═O)NR c —, —OC(R b ) 2 —, —C(R b ) 2 O—, —SC(R b ) 2 —, —C(R b ) 2 S—, —NR c C(R b ) 2 —, —C(R b ) 2 NR c —, —S(═O)O—, —OS(═O)—, —S(═O)NR c —, —NR c S(═O)—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR c —, —NR c S(═O) 2 —, —OC(═O)O—, —NR c C(═O)O—, —OC(═O)NR c —, —NR c C(═O)NR c —, —C(R b ) 2 C(═O)C(R b ) 2 —, —OC(═O)C(R b ) 2 —, —C(R b ) 2 C(═O)O—, —NR c C(═O)C(R b ) 2 —, —C(R b ) 2 C(═O)NR c —, or a substituted or unsubstituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —NR c —;
each instance of R D 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 ;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
R E is of the formula:
L 3 is —C(R b ) 2 —, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR c —, —C(R b ) 2 C(R b ) 2 —, —C(R b ) 2 C(═O)—, —C(═O)C(R b ) 2 —, (E)-CR b ═CR b —, (Z)—CR b ═CR b —, —C≡C—, —OC(═O)—, —C(═O)O—, —SC(═O)—, —C(═O)S—, —NR c C(═O)—, —C(═O)NR c —, —OC(R b ) 2 —, —C(R b ) 2 O—, —SC(R b ) 2 —, —C(R b ) 2 S—, —NR c C(R b ) 2 —, —C(R b ) 2 NR c —, —S(═O)O—, —OS(═O)—, —S(═O)NR c —, —NR c S(═O)—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR c —, —NR c S(═O) 2 —, —OC(═O)O—, —NR c C(═O)O—, —OC(═O)NR c —, —NR c C(═O)NR c —, —C(R b ) 2 C(═O)C(R b ) 2 —, —OC(═O)C(R b ) 2 —, —C(R b ) 2 C(═O)O—, —NR c C(═O)C(R b ) 2 —, —C(R b ) 2 C(═O)NR c —, or a substituted or unsubstituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —NR c —;
L 4 is a bond or substituted or unsubstituted C 1-6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 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, —CN, —CH 2 OR a , —CH 2 N(R a ) 2 , —CH 2 SR a , —OR a , —N(R a ) 2 , —SR a , or —Si(R a ) 3 ; or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form a substituted or unsubstituted, carbocyclic ring, or substituted or unsubstituted, heterocyclic ring;
R E4 is a leaving group;
R E5 is halogen;
R E6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of Y is independently O, S, or NR c ;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.
2 . The compound of claim 1 , wherein Ring C is a substituted or unsubstituted phenyl ring, substituted or unsubstituted, monocyclic carbocyclic ring, or substituted or unsubstituted, monocyclic heterocyclic ring.
3 . The compound of claim 1 or 2 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 or 2 , wherein the compound is of Formula (II-a):
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 or 2 , wherein the compound is of Formula (II-b):
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 or 2 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 or 2 , wherein the compound is of Formula (III-a):
or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 or 2 , wherein the compound is of Formula (III-b):
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 or 2 , wherein the compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 1 or 2 , wherein the compound is of Formula (IV-a):
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 or 2 , wherein the compound is of Formula (V):
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 1 or 2 , wherein the compound is of Formula (V-a):
or a pharmaceutically acceptable salt thereof.
19 . The compound of claim 1 or 2 , wherein the compound is of Formula (V-b):
or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 1 or 2 , wherein the compound is of Formula (VI):
or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 1 or 2 , wherein the compound is of Formula (VI-a):
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 1 or 2 , wherein the compound is of the formula
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
26 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
27 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
29 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
30 . The compound of claim 1 or 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
31 . The compound of any one of claims 1 - 30 , wherein Ring A is a substituted or unsubstituted, bicyclic heteroaryl ring.
32 . The compound of claim 31 , wherein Ring A is a substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
33 . The compound of claim 31 , wherein Ring A is a substituted or unsubstituted, bicyclic heteroaryl ring with one nitrogen.
34 . The compound of claim 31 , wherein Ring A is of Formula (A-i):
wherein:
each instance of R A1 is independently selected from the group consisting of 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, and a nitrogen protecting group; and
each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, 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, —CN, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from the group consisting of 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, and a sulfur protecting group when attached to a sulfur atom, or two R A2a groups are joined to form a substituted or unsubstituted heterocyclic ring.
35 . The compound of claim 31 , wherein Ring A is of the formula:
36 . The compound of claim 31 , wherein Ring A is a substituted or unsubstituted, bicyclic heteroaryl ring with two nitrogen.
37 . The compound of claim 31 , wherein Ring A is of Formula (A-ii):
wherein:
each instance of R A1 is independently selected from the group consisting of 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, and a nitrogen protecting group; and
each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, 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, —CN, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from the group consisting of 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, and a sulfur protecting group when attached to a sulfur atom, or two R A2a groups are joined to form a substituted or unsubstituted heterocyclic ring.
38 . The compound of claim 31 , wherein Ring A is of the formula:
39 . The compound of claim 31 , wherein Ring A is of Formula (A-iii):
wherein:
each instance of R A1 is independently selected from the group consisting of 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, and a nitrogen protecting group; and
each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, 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, —CN, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from the group consisting of 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, and a sulfur protecting group when attached to a sulfur atom, or two R A2a groups are joined to form a substituted or unsubstituted heterocyclic ring.
40 . The compound of claim 31 , wherein Ring A is of the formula:
41 . The compound of any one of claims 1 - 30 , wherein Ring A is a substituted or unsubstituted, monocyclic heteroaryl ring.
42 . The compound of claim 41 , wherein Ring A is a substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
43 . The compound of claim 41 , wherein Ring A is a substituted or unsubstituted, monocyclic heteroaryl ring with one nitrogen.
44 . The compound of claim 41 , wherein Ring A is of Formula (A-v):
wherein:
each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, 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, —CN, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from the group consisting of 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, and a sulfur protecting group when attached to a sulfur atom, or two R A2a groups are joined to form a substituted or unsubstituted heterocyclic ring.
45 . The compound of claim 41 , wherein Ring A is of the formula:
46 . The compound of any one of claims 1 - 45 , wherein L 1 is a bond.
47 . The compound of any one of claims 1 - 45 , wherein L 1 is —O—.
48 . The compound of any one of claims 1 - 45 , wherein L 1 is —S—.
49 . The compound of any one of claims 1 - 45 , wherein L 1 is —NR c —.
50 . The compound of claim 49 , wherein L 1 is —NH—.
51 . The compound of any one of claims 1 - 50 , wherein R B1 is hydrogen.
52 . The compound of any one of claims 1 - 50 , wherein R B1 is —N(R a ) 2 .
53 . The compound of claim 52 , wherein R B1 is —NH 2 .
54 . The compound of any one of claims 1 - 53 , wherein R B2 is hydrogen.
55 . The compound of any one of claims 1 - 54 , wherein X is —NR c —.
56 . The compound of claim 55 , wherein X is —NH—.
57 . The compound of any one of claims 1 - 56 , wherein Ring C is a substituted or unsubstituted phenyl ring.
58 . The compound of any one of claims 1 - 56 , wherein Ring C is a substituted or unsubstituted, monocyclic carbocyclic ring.
59 . The compound of claim 58 , wherein Ring C is a substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclic ring, wherein there are zero, one, or two double bonds in the carbocyclic ring system, as valency permits.
60 . The compound of claim 58 , wherein Ring C is substituted or unsubstituted cyclohexylene.
61 . The compound of any one of claims 1 - 56 , wherein Ring C is a substituted or unsubstituted, monocyclic heterocyclic ring.
62 . The compound of claim 61 , wherein Ring C is a substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
63 . The compound of claim 61 , wherein Ring C is substituted or unsubstituted piperidinylene.
64 . The compound of any one of claims 1 - 56 , wherein Ring C is a substituted or unsubstituted, monocyclic heteroaryl ring.
65 . The compound of claim 64 , wherein Ring C is a substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
66 . The compound of claim 64 , wherein Ring C is substituted or unsubstituted pyridinylene.
67 . The compound of claim 64 , wherein Ring C is substituted or unsubstituted 2-pyridinylene, wherein X is attached to the 1-position of the substituted or unsubstituted 2-pyridinylene.
68 . The compound of any one of claims 1 - 67 , wherein L 2 is —NR c C(═O)— or —C(═O)NR c —.
69 . The compound of claim 68 , wherein L 2 is —NR c C(═O)—.
70 . The compound of claim 68 , wherein L 2 is —NHC(═O)— or —C(═O)NH—.
71 . The compound of claim 68 , wherein L 2 is —NHC(═O)—.
72 . The compound of any one of claims 1 - 67 , wherein L 2 is —C(═O)—.
73 . The compound of any one of claims 1 - 67 , wherein L 2 is —C(R b ) 2 —.
74 . The compound of claim 73 , wherein L 2 is —CH 2 —.
75 . The compound of any one of claims 1 - 67 , wherein L 2 is —C(R b ) 2 C(═O)—.
76 . The compound of claim 75 , wherein L 2 is —CH 2 C(═O)—.
77 . The compound of any one of claims 1 - 67 , wherein L 2 is —C(R b ) 2 C(═O)NR c —.
78 . The compound of claim 77 , wherein L 2 is —CH 2 C(═O)NH—.
79 . The compound of any one of claims 1 - 78 , wherein X and L 2 are para to each other.
80 . The compound of any one of claims 1 - 78 , wherein X and L 2 are meta to each other.
81 . The compound of any one of claims 1 - 80 , wherein R E and L 2 are para to each other.
82 . The compound of any one of claims 1 - 80 , wherein R E and L 2 are meta to each other.
83 . The compound of any one of claims 1 - 82 , wherein Ring D is a substituted or unsubstituted phenyl ring.
84 . The compound of any one of claims 1 - 82 , wherein Ring D is a substituted or unsubstituted, monocyclic carbocyclic ring.
85 . The compound of claim 84 , wherein Ring D is a substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclic ring, wherein there are zero, one, or two double bonds in the carbocyclic ring system, as valency permits.
86 . The compound of claim 84 , wherein Ring D is substituted or unsubstituted cyclohexylene.
87 . The compound of any one of claims 1 - 82 , wherein Ring D is a substituted or unsubstituted, monocyclic heterocyclic ring.
88 . The compound of claim 87 , wherein Ring D is a substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
89 . The compound of claim 87 , wherein Ring D is substituted or unsubstituted piperidinylene.
90 . The compound of any one of claims 1 - 89 , wherein R E is of Formula (i-18):
91 . The compound of claim 90 , wherein L is —NR c C(═O)—.
92 . The compound of claim 90 , wherein L 3 is —NHC(═O)—.
93 . The compound of any one of claims 90 - 92 , wherein R E1 is hydrogen.
94 . The compound of any one of claims 90 - 93 , wherein R E2 is hydrogen.
95 . The compound of any one of claims 90 - 94 , wherein R E3 is optionally substituted alkyl.
96 . The compound of claim 95 , wherein R E3 is substituted alkyl.
97 . The compound of claim 95 , wherein R E3 is —CH 2 —N(CH 3 ) 2 .
98 . The compound of claim 90 , wherein R E is of the formula:
99 . The compound of claim 90 , wherein R E is of the formula:
100 . The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
101 . The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
102 . The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
103 . A pharmaceutical composition comprising a compound of any one of claims 1 - 102 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
104 . The pharmaceutical composition of claim 103 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for use in treating a proliferative disease in a subject in need thereof.
105 . A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 102 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 103 and 104 .
106 . The method of claim 105 , wherein the subject is a mammal.
107 . The method of claim 105 , wherein the subject is a human.
108 . The method of any one of claims 105 - 107 , wherein the proliferative disease is associated with aberrant activities of a kinase.
109 . The method of any one of claims 105 - 108 , wherein the proliferative disease is cancer.
110 . The method of claim 109 , wherein the cancer is breast cancer.
111 . The method of claim 109 , wherein the cancer is lung cancer.
112 . The method of claim 109 , wherein the cancer is small cell lung cancer (SCLC).
113 . The method of claim 109 , wherein the cancer is non-small cell lung cancer (NSCLC).
114 . A method of modulating the activity of a kinase in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of any one of claims 1 - 102 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 103 and 104 .
115 . The method of any one of claims 108 and 114 , wherein the kinase is a protein kinase.
116 . The method of claim 115 , wherein the protein kinase is a cyclin-dependent kinase (CDK).
117 . The method of claim 116 , wherein the protein kinase is CDK7.
118 . The method of claim 116 , wherein the protein kinase is CDK12.
119 . The method of claim 116 , wherein the protein kinase is CDK13.
120 . The method of any one of claims 108 and 114 , wherein the kinase is a lipid kinase.
121 . The method of claim 120 , wherein the lipid kinase is a phosphatidylinositol phosphate kinase (PIPK).
122 . The method of claim 121 , wherein the PIPK is PIP4K2.
123 . The method of claim 121 , wherein the PIPK is PI5P4Kα.
124 . The method of claim 121 , wherein the PIPK is PI5P4Kβ.
125 . The method of claim 121 , wherein the PIPK is PI5P4Kγ.
126 . The method of any one of claims 105 - 125 , wherein the compound is capable of covalently modifying Cys293 of PI5P4Kα.
127 . The method of any one of claims 105 - 125 , wherein the compound is capable of covalently modifying Cys307 and/or Cys318 of PI5P4Kβ.
128 . The method of any one of claims 105 - 125 , wherein the compound is capable of covalently modifying Cys313 of PI5P4Kγ.
129 . A method of inhibiting cell growth in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of any one of claims 1 - 102 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 103 and 104 .
130 . The method of any one of claims 105 - 129 , further comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of one or more pharmaceutical agents in combination with the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
131 . The method of claim 130 , wherein the pharmaceutical agent is an anti-proliferative agent.
132 . The method of claim 130 , wherein the pharmaceutical agent is a kinase inhibitor.
133 . The method of claim 130 , wherein the pharmaceutical agent is an inhibitor of a protein kinase.
134 . The method of claim 130 , wherein the pharmaceutical agent is an inhibitor of cyclin-dependent kinase (CDK).
135 . The method of claim 130 , wherein the pharmaceutical agent is an inhibitor of a lipid kinase.
136 . The method of claim 130 , wherein the pharmaceutical agent is an inhibitor of a phosphatidylinositol phosphate kinase (PIPK).
137 . A kit comprising:
a compound of any one of claims 1 - 102 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 103 and 104 ; and instructions for administering to a subject or contacting a biological sample with the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.Join the waitlist — get patent alerts
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