US2020338074A1PendingUtilityA1
Combination therapy of transcription inhibitors and kinase inhibitors
Assignee: DANA FARBER CANCER INST INCPriority: Jun 12, 2015Filed: May 26, 2020Published: Oct 29, 2020
Est. expiryJun 12, 2035(~8.9 yrs left)· nominal 20-yr term from priority
A61K 31/4162A61P 35/00A61K 31/519A61K 31/506A61K 31/69A61K 31/5517A61K 31/53A61K 45/06A61K 31/52A61K 31/551
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Claims
Abstract
The present disclosure provides combination therapy of a transcription inhibitor and a kinase inhibitor. The combination of the transcription inhibitor and the kinase inhibitor may be useful in treating and/or preventing in a subject a proliferative disease, such as proliferative a disease that is resistant to the transcription inhibitor alone or the kinase inhibitor alone. In certain embodiments, the proliferative disease is a cancer. The combination of the transcription inhibitor and the kinase inhibitor is expected to be synergistic.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of:
a transcription inhibitor; and a kinase inhibitor; wherein the transcription inhibitor and the kinase inhibitor are not the same.
2 . The method of claim 1 , wherein the transcription inhibitor and the kinase inhibitor are synergistic in treating the proliferative disease, compared to the transcription inhibitor alone or the kinase inhibitor alone.
3 . The method of any one of claims 1 - 2 , wherein the proliferative disease is resistant to the kinase inhibitor.
4 . A method of reducing, delaying, or preventing in a subject in need thereof the resistance of a proliferative disease to a kinase inhibitor, the method comprising administering to the subject an effective amount of:
a transcription inhibitor; and the kinase inhibitor; wherein the transcription inhibitor and the kinase inhibitor are not the same.
5 . The method of claim 4 , wherein the transcription inhibitor and the kinase inhibitor are synergistic in reducing, delaying, or preventing the resistance of the proliferative disease to the kinase inhibitor, compared to the transcription inhibitor alone or the kinase inhibitor alone.
6 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is a cyclin-dependent kinase (CDK) inhibitor.
7 . The method of claim 6 , wherein the transcription inhibitor is a CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, or CDK12 inhibitor.
8 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is a bromodomain-containing protein inhibitor.
9 . The method of claim 8 , wherein the bromodomain-containing protein inhibitor is a bromodomain-containing protein 2 (BRD2) inhibitor, bromodomain-containing protein 3 (BRD3) inhibitor, bromodomain-containing protein 4 (BRD4) inhibitor, TBP (TATA box binding protein)-associated factor protein (TAP) inhibitor, CREB-binding protein (CBP) inhibitor, or E1A binding protein p300 (EP300) inhibitor.
10 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted heteroaryl ring of any one of the Formulae (i-1)-(i-5):
each instance of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , V 9 , V 10 , V 11 , V 12 , V 13 , and V 14 is independently O, S, N, NR A1 , C, or CR A2 ;
each instance of R A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;
each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 an optionally substituted heterocyclic ring;
optionally any two of R A1 , R A2 , and R A2a groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
Ring B is of the formula:
R B1 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 B1a groups are joined to form an optionally substituted heterocyclic ring;
W B is N or CR B2 , wherein R B2 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B2a , —N(R B2a ) 2 , and —SR B2a , wherein each occurrence of R B2a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 B2a groups are joined to form an optionally substituted heterocyclic ring;
optionally R B1 and R B2 are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl ring;
X is an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, or —NR X —, wherein R X is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;
L 2 is a bond, —O—, —S—, —NR L2a —, —NR L2a C(═O)—, —C(═O)NR L2a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L2a C(═S)—, —C(═S)NR L2a —, trans-CR L2b ═CR L2b —, cis-CR L2b ═CR L2b —, —C≡C—, —OC(R L2b ) 2 —, —C(R L2b ) 2 O—, —NR L2a C(R L2b ) 2 —, —C(R L2b ) 2 NR L2a —, —SC(R L2b ) 2 —, —C(R L2b ) 2 S—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L2a —, —NR L2a S(═O) 2 —, or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR L2a —, —NR L2a C(═O)—, —C(═O)NR L2a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L2a C(═S)—, —C(═S)NR L2a —, trans-CR L2b ═CR L2b —, cis-CR L2b ═CR L2b —, —C≡C—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L2a —, or —NR L2a S(═O) 2 —, wherein R L2a is hydrogen, C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L2b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R L2b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
each instance of R C is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 C1 groups are joined to form an optionally substituted heterocyclic ring;
n is 0, 1, 2, 3, or 4;
each instance of R D is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 D1 groups are joined to form an optionally substituted heterocyclic ring;
p is 0, 1, 2, 3, or 4;
R E is any one of the Formulae (ii-1)-(ii-17):
R E and L 2 are para or meta to each other;
L 3 is a bond, —O—, —S—, —NR L3a — or an optionally substituted C 4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted C 1-4 hydrocarbon chain;
R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , and —SR E1a , wherein each occurrence of R E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a groups are joined to form an optionally substituted heterocyclic ring;
R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a groups are joined to form an optionally substituted heterocyclic ring;
R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a groups are joined to form an optionally substituted heterocyclic ring;
optionally R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
R E4 is a leaving group;
Y is O, S, or NR E5 , wherein R E5 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
z is 0, 1, 2, 3, 4, 5, or 6.
11 . The method of claim 10 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
12 . The method of claim 10 , wherein the transcription inhibitor is of the formula: ‘ ’
or a pharmaceutically acceptable salt thereof.
13 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
G is group of atoms ranging a total length between 20 to 30 {acute over (Å)};
R E is an electrophile with any one of the Formulae (ii-1)-(ii-17):
L 3 is a bond, —O—, —S—, —NR L3a —, or an optionally substituted hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR 13 —, —NR 13a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted C 1-4 hydrocarbon chain;
R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , and —SR E1a , wherein each occurrence of R E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a groups are joined to form an optionally substituted heterocyclic ring;
R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a groups are joined to form an optionally substituted heterocyclic ring;
R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a groups are joined to form an optionally substituted heterocyclic ring;
optionally R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
R E4 is a leaving group;
Y is O, S, or NR E5 , wherein R E5 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
z is 0, 1 or 2;
L 1e is a linker ranging between 0 to 3 atoms in length;
L x is a linker ranging between 0 to 5 atoms in length;
optionally, the IC 50 for CDK7 is less than approximately 100 nM; and
optionally, the CDK inhibitor is selective for CDK7.
14 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted heteroaryl ring of any one of the Formulae (i-1)-(i-6):
wherein:
each instance of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , V 9 , V 10 , V 11 , V 12 , V 13 , V 14 , and V 15 is independently O, S, N, NR A1 , C, or CR A2 ;
each instance of R A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;
each instance of R 42 is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 an optionally substituted heterocyclic ring; and
optionally any two of R A1 , R A2 , and R A2a groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
R B1 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 R B1 and R B2 are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
W B is N or CR B2 , wherein R B2 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR B2a , —N(R B2a ) 2 , and —SR B2a , or R B2 and R B1 are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring, wherein each occurrence of R B2a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 B2a groups are joined to form an optionally substituted heterocyclic ring;
L 1 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the optionally substituted C 1-4 hydrocarbon chain are independently replaced with —O—, —S—, —NR L1 —, —S(═O)—, or —S(═O) 2 —, wherein R L1 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and optionally wherein two substituents on the optionally substituted C 1-4 hydrocarbon chain are taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 2 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the optionally substituted C 1-4 hydrocarbon chain are independently replaced with —O—, —S—, —NR 12 —, —S(═O)—, or —S(═O) 2 —, wherein R 12 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and optionally wherein two substituents on the optionally substituted C 1-4 hydrocarbon chain are taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
each instance of R C is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, ═O, —CN, —OR C1 , —N(R C1 ) 2 , and —SR C1 ; or two R C groups are taken together to form an optionally substituted, carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein two substituents on the substituted heterocyclic ring or substituted carbocyclic ring, or one substituent on the substituted heterocyclic ring or substituted carbocyclic ring and a third R C group, are taken together to form another optionally substituted heterocyclic ring or optionally substituted carbocyclic ring; wherein each occurrence of R C1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 C1 groups are joined to form an optionally substituted heterocyclic ring;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
each instance of R D is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted 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 D1 groups are joined to form an optionally substituted heterocyclic ring;
p is 0, 1, 2, 3, or 4;
R E is of any one of the Formulae (ii-1)-(ii-20):
L 3 is a bond, —O—, —S—, —NR L3a —, or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —O—, —S—, —NR L3b —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted C 1-4 hydrocarbon chain;
R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , —Si(R E1a ) 3 , and —SR E1a , wherein each occurrence of R E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a groups are joined to form an optionally substituted heterocyclic ring;
R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a groups are joined to form an optionally substituted heterocyclic ring;
R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a groups are joined to form an optionally substituted heterocyclic ring;
optionally R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
R E4 is a leaving group;
R E5 is halogen;
Y is O, S, or NR E6 , wherein R E6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
z is 0, 1, 2, 3, 4, 5, or 6.
15 . The method of claim 14 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
16 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (IV):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
Ring A is an optionally substituted heteroaryl ring of any one of the Formulae (i-1)-(i-6):
(i-6), wherein:
each instance of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , V 9 , V 10 , V 11 , V 12 , V 13 , V 14 and V 15 is independently O, S, N, N(R A1 ), C, or C(R A2 ):
each instance of R A1 is independently selected from hydrogen, deuterium, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each instance of R M is independently selected from hydrogen, deuterium, halogen, —CN, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A3a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
any two R A1 , any two R A2 , or one R A1 and one R A2 are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
each X is independently selected from N and CH, wherein at least one X is N;
W is selected from N and C(R 1a );
each of R 1a , if present, and R 1b is independently selected from hydrogen, deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R 1a and R 1b are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
R 2 is an optionally substituted C 1 -C 4 alkylene or an optionally substituted C 2 -C 4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R 6 )—;
each instance of R 3 , if present, is independently selected from deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1 is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
two R 3 groups bound to the same ring carbon atom are taken together to form ═O, or
two R 3 groups bound to the same or different ring carbon atoms are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
R 4 is selected from a bond, an optionally substituted C 1 -C 4 alkylene, and an optionally substituted C 2 -C 4 alkenylene or alkynylene, wherein:
one or more methylene units of the alkylene, alkenylene or alkynylene other than a methylene unit bound to a nitrogen atom is optionally and independently replaced with —O—, —S—, —N(R 6 )—, or —S(═O) 2 —, and
two substituents on either the same or adjacent carbon atoms in the alkylene, alkenylene or alkynylene are taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
each R 6 is independently selected from hydrogen, and —C 1 -C 6 alkyl;
R 7 is any one of the Formulae (ii-1)-(ii-20):
wherein:
L 3 is a bond, an optionally substituted C 1 -C 4 alkylene, or an optionally substituted C 2 -C 4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R 6 )—;
L 4 is a bond, an optionally substituted C 1 -C 4 alkylene, or an optionally substituted C 2 -C 4 alkenylene or alkynylene;
R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , —Si(R E1a ) 3 , and —SR E1a , wherein each occurrence of R E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a groups are joined to form an optionally substituted heterocyclic ring;
R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a groups are joined to form an optionally substituted heterocyclic ring;
R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a groups are joined to form an optionally substituted heterocyclic ring;
optionally R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
R E4 is a leaving group;
R E5 is halogen;
Y is O, S, or NR E6 , wherein R E6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2;
z is 0, 1, 2, 3, 4, 5, or 6;
each instance of R 8 , if present, is independently selected from deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1 is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, and optionally substituted aryl, optionally substituted heteroaryl, or
two R 8 groups are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
m is 0, 1, 2, 3 or 4; and
n is 0, 1, 2, 3, 4, 5 or 6.
17 . The method of claim 16 , wherein the transcription inhibitor is of formula:
or a pharmaceutically acceptable salt thereof.
18 . The method of claim 16 , wherein the transcription inhibitor is of formula:
or a pharmaceutically acceptable salt thereof.
19 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (V):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —NR a R b , —CHR a R b or —OR a , wherein each of R a and R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or R a and R b are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
each of R 3 and R 4 is independently hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl, or R 3 and R 4 are joined to form an optionally substituted C 3 -C 6 carbocyclyl ring;
R 5 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
L 1 is —NR L1 —, —NR L1 C(═O)—, —C(═O)NR L1 —, —O—, or —S—, wherein R L1 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L 2 is a bond, —C(═O)—, —NR L2 —, —C(═O)NR L2 —, —NR L2 C(═O)—, —O—, or —S—, wherein R L2 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 2 is any of Formulae (i-1)-(i-46):
wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted, branched or unbranched C 1-6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR EE , —CH 2 N(R EE ) 2 , —CH 2 SR ee , —OR ee , —N(R ee ) 2 , —Si(R EE ) 3 , and -SR™, wherein each occurrence of R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring;
or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted 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 E7 , wherein R E7 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
20 . The method of claim 19 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
21 . The method of claim 19 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
22 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NR a R b , —OR b , —SR b , —C(═O)R b , —C(═O)OR b , or —C(═O)NR a R b , wherein each instance of R a and R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to nitrogen, or an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or R a and R b are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
R 3 is hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
R 5 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
L 1 is a bond, —NR L1 —(CH 2 ) t , —O—, or —S—;
R L1 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
t is 0 or an integer between 1 and 5, inclusive;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L 2 is a bond, optionally substituted C 1-4 alkylene, —C(═O)—, —NR L2 —, —C(═O)NR L2 —, —NR L2 C(═O)—, —O—, or —S—, wherein R L2 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 2 is any of Formulae (i-1)-(i-46):
wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted, branched or unbranched C 1-6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR EE , —CH 2 N(R EE ) 2 , —CH 2 SR EE , —OR ee , —N(R ee ) 2 , —Si(R BE ) 3 , and —SR EE , wherein each occurrence of R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring;
or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted 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 E7 , wherein R E7 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
23 . The method of claim 22 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
24 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (VII):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NR a R b , —OR b , —SR b , —C(═O)R b , —C(═O)OR b , or —C(═O)NR a R b , wherein each instance of R a and R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to nitrogen, or an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or R a and R b are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each of R 3 and R 4 is independently hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
L 1 is a bond, —NR L1 —(CH 2 ) t , —O—, or —S—;
R L1 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
t is 0 or an integer between 1 and 5, inclusive;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L 2 is a bond, optionally substituted C 1-4 alkylene, —C(═O)—, —NR L2 —, —C(═O)NR L2 —, —NR L2 C(═O)—, —O—, or —S—, wherein R L2 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 2 is any of Formulae (i-1)-(i-46):
wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted, branched or unbranched C 1-6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR EE , —CH 2 N(R EE ) 2 , —CH 2 SR EE , —OR ee , —N(R ee ) 2 , —Si(R BE ) 3 , and —SR EE , wherein each occurrence of R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring;
or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted 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 E7 , wherein R E7 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
25 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (VIII):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NR a R b , —OR b , —SR b , —C(═O)R b , —C(═O)OR b , or —C(═O)NR a R b , wherein each instance of R a and R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to nitrogen, or an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or R a and R b are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each of R 3 and R 4 is independently hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
R 5 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
L 1 is a bond, —NR L1 —(CH 2 ) t , —O—, or —S—;
R L1 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
t is 0 or an integer between 1 and 5, inclusive;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L 2 is a bond, optionally substituted C 1-4 alkylene, —C(═O)—, —NR L2 —, —C(═O)NR L2 —, —NR L2 C(═O)—, —O—, or —S—, wherein R L2 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 2 is any of formulae (i-1)-(i-46):
wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O)NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted, branched or unbranched C 1-6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR EE , —CH 2 N(R EE ) 2 , —CH 2 SR EE , —OR ee , —N(R ee ) 2 , —Si(R BE ) 3 , and —SR EE , wherein each occurrence of R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring;
or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
R 14 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 E7 , wherein R E7 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
26 . The method of claim 25 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
27 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
28 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (IX):
or a pharmaceutically acceptable salt thereof, wherein:
X A is C(R D ) or N;
X B is C(R D ) or N;
X C is C(R D ) or N;
wherein no more than two of X A , X B , and X C can be N;
Ring A is of the formula:
L is a bond or of the formula:
each instance of R A is independently 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, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 , or two instances of R A are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
each instance of R A1 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 A1 are joined to form a substituted or unsubstituted heterocyclic ring;
R B is 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, —C(═O)R B1 , —C(═O)OR B1 , —C(═O)N(R B1 ) 2 , or a nitrogen protecting group, or R B and R C are joined to form a substituted or unsubstituted heterocyclic ring;
each instance of R B1 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of R B1 are joined to form a substituted or unsubstituted heterocyclic ring;
R C is 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, —C(═O)R C1 , —C(═O)OR C1 , —C(═O)N(R C1 ) 2 , or a nitrogen protecting group, or R C and R B are joined to form a substituted or unsubstituted heterocyclic ring;
each instance of R C1 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of R C1 are joined to form a substituted or unsubstituted heterocyclic ring;
each instance of R D is independently 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, —OR D1 , —N(R D1 ) 2 , —SR D1 , —CN, —SCN, —C(═NR D1 )R D1 , —C(═NR D1 )OR D1 , —C(═NR D1 )N(R D1 ) 2 , —C(═O)R D1 , —C(═O)OR D1 , —C(═O)N(R D1 ) 2 , —NO 2 , —NR D1 C(═O)R D1 , —NR D1 C(═O)OR D1 , —NR D1 C(═O)N(R D1 ) 2 , —OC(═O)R D1 , —OC(═O)OR D1 , or —OC(═O)N(R D1 ) 2 , or two instances of R D are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
each instance of R D1 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 D1 are joined to form a substituted or unsubstituted heterocyclic ring;
R E is 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, —C(═O)R E1 , —C(═O)OR E1 , —C(═O)N(R E1 ) 2 , or a nitrogen protecting group;
each instance of R E1 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of R D1 are joined to form a substituted or unsubstituted heterocyclic ring;
each instance of R F is independently 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, —OR F1 , —N(R F1 ) 2 , —SR F1 , —CN, —SCN, —C(═NR F1 )R F1 , —C(═NR F1 )OR F1 , —C(═NR F1 )N(R F1 ) 2 , —C(═O)R F1 , —C(═O)OR F1 , —C(═O)N(R F1 ) 2 , —NO 2 , —NR F1 C(═O)R F1 , —NR F1 C(═O)OR F1 , —NR F1 C(═O)N(R F1 ) 2 , —OC(═O)R F1 , —OC(═O)OR F1 , or —OC(═O)N(R F1 ) 2 , or two instances of R F are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
each instance of R F1 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 F1 are joined to form a substituted or unsubstituted heterocyclic ring;
a is 0, 1, 2, 3, 4, or 5;
d is 0, 1, or 2;
f is 0, 1, 2, 3 or 4; and
g is 0, 1, 2, or 3.
29 . The method of claim 28 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
30 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
31 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (X):
or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
X 1 is —O—, —S—, or —C(R X1 ) 2 —, wherein each instance of R X1 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
Y 1 is N or CR Y1 , wherein R Y1 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
Z 1 is —O—, —N(R Z1 )— or —C(R Z1 ) 2 —, wherein each instance of R Z1 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubslituled carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R Z1 are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;
each instance of R A1 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 A1a , —N(R A1a ) 2 , —SR A1a , —CN, —SCN, —C(═NR A1a )R A1a , —C(═NR A1a )OR A1a , —C(═NR A1a )N(R A1a ) 2 , —C(═O)R A1a , —C(═O)OR A1a , —C(═O)N(R A1a ) 2 , —NO 2 , —NR A1a C(═O)R A1a , —NR A1a C(═O)OR A1a , —NR A1a C(═O)N(R A1a ) 2 , —OC(═O)R A1a , —OC(═O)OR A1a , or —OC(═O)N(R A1a ) 2 , wherein each instance of R A1a 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 A1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
a is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
each instance of R B1 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 B1a , —N(R B1a ) 2 , —SR B1a , —CN, —SCN, —C(═NR B1a )R B1a , —C(═NR B1a )OR B1a , —C(═NR B1a )N(R B1a ) 2 , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)N(R B1a ) 2 , —NO 2 , —NR B1a C(═O)R B1a , —NR B1a C(═O)OR B1a , —NR B1a C(═O)N(R B1a ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , or —OC(═O)N(R B1a ) 2 , wherein each instance of R B1a 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 B1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
b is 0, 1, 2, or 3;
R C1 is 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, or an oxygen protecting group;
R D1 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 D1a , —N(R D1a ) 2 , —SR D1a , —CN, —SCN, —C(═NR D1a )R D1a , —C(═NR D1a )OR D1a , —C(═NR D1a )N(R D1a ) 2 , —C(═O)R D1a , —C(═O)OR D1a , —C(═O)N(R D1a ) 2 , —NO 2 , —NR D1a C(═O)R D1a , —NR D1a C(═O)OR D1a , —NR D1a C(═O)N(R D1a ) 2 , —OC(═O)R D1a , —OC(═O)OR D1a , or —OC(═O)N(R D1a ) 2 , wherein each instance of R D1a 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 D1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R E1 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;
R F1 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;
R G1 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; and
R H1 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
or R G1 and R H1 are joined to form a substituted or unsubstituted phenyl ring.
32 . The method of claim 31 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
33 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
W 2 is —S(═O)OR W2 , —S(═O)N(R W2 ) 2 , —S(═O) 2 OR W2 , —S(═O) 2 N(R W2 ) 2 ,
each instance of R W2 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, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R W2 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
R V2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
U 2 is R B2 or —OR C2 ;
X 2 is —O—, —S—, —N(R X2 )—, or —C(R X2 ) 2 —, wherein each instance of R X2 is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group when attached to a nitrogen atom;
Z 2 is —O—, —N(R Z2 )— or —C(R Z2 ) 2 —, wherein each instance of R Z2 is independently 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, or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R Z2 are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;
each instance of R A2 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 A2a , —N(R A2a ) 2 , —SR A2a , —CN, —SCN, —C(═NR A2a )R A2a , —C(═NR A2a )OR A2a , —C(═NR A2a )N(R A2a ) 2 , —C(═O)R A2a , —C(═O)OR A2a , —C(═O)N(R A2a ) 2 , —NO 2 , —NR A2a C(═O)R A2a , —NR A2a C(═O)OR A2a , —NR A2a C(═O)N(R A2a ) 2 , —OC(═O)R A2a , —OC(═O)OR A2a , or —OC(═O)N(R A2a ) 2 , wherein each instance of R A3a 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 A2a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
each instance of R B2 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 B2a , —N(R B2a ) 2 , —SR B2a , —CN, —SCN, —C(═NR B2a )R B2a , —C(═NR B2a )OR B2a , —C(═NR B2a )N(R B2a ) 2 , —C(═O)R B2a , —C(═O)OR B2a , —C(═O)N(R B2a ) 2 , —NO 2 , —NR B2a C(═O)R B2a , —NR B2a C(═O)OR B2a , —NR B2a C(═O)N(R B2a ) 2 , —OC(═O)R B2a , —OC(═O)OR B2a , or —OC(═O)N(R B2a ) 2 , wherein each instance of R B2a 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 B2a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
m is 0, 1, 2, or 3;
R C2 is 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, or an oxygen protecting group;
each instance of R D2 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 D2a , —N(R D2a ) 2 , —SR D2a , —CN, —SCN, —C(═NR D2a )R D2a , —C(═NR D2a )OR D2a , —C(═NR D2a )N(R D2a ) 2 , —C(═O)R D2a , —C(═O)OR D2a , —C(═O)N(R D2a ) 2 , —NO 2 , —NR D2a C(═O)R D2a , —NR D2a C(═O)OR D2a , —NR D2a C(═O)N(R D2a ) 2 , —OC(═O)R D2a , —OC(═O)OR D2a , or —OC(═O)N(R D2a ) 2 , wherein each instance of R D2a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubslituled 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 D2a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
n is 0, 1, or 2;
R E2 is hydrogen, substituted or unsubslituled 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, 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 G2 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; and
R H2 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
or R G2 and R H2 are joined to form a substituted or unsubstituted phenyl ring.
34 . The method of claim 33 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
35 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XII):
or a pharmaceutically acceptable salt thereof, wherein:
each instance of is independently a single or double bond;
X 3 is —O—, —S—, —N(R X3 )—, or —C(R X3 ) 2 —, wherein each instance of R X3 is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group when attached to a nitrogen atom;
Y 3 is N or CR Y3 , wherein R Y3 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
Z 3 is —O—, —N(R Z3 )— or —C(R Z3 ) 2 —, wherein each instance of R Z3 is independently 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, or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R Z3 are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;
each instance of R A3 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 A3a , —N(R A3a ) 2 , —SR A3a , —CN, —SCN, —C(═NR A3a )R A3a , —C(═NR A3a )OR A3a , —C(═NR A3a )N(R A3a ) 2 , —C(═O)R A3a , —C(═O)OR A3a , —C(═O)N(R A3a ) 2 , —NO 2 , —NR A3a C(═O)R A3a , —NR A3a C(═O)OR A3a , —NR A3a C(═O)N(R A3a ) 2 , —OC(═O)R A3a , —OC(═O)OR A3a , or —OC(═O)N(R A3a ) 2 , wherein each instance of R A2a 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 A3a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
p is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
each instance of R B3 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 B3a , —N(R B3a ) 2 , —SR B3a , —CN, —SCN, —C(═NR B3a )R B3a , —C(═NR B3a )OR B3a , —C(═NR B3a )N(R B3a ) 2 , —C(═O)R B3a , —C(═O)OR B3a , —C(═O)N(R B3a ) 2 , —NO 2 , —NR B3a C(═O)R B3a , —NR B3a C(═O)OR B3a , —NR B3a C(═O)N(R B3a ) 2 , —OC(═O)R B3 , —OC(═O)OR B3a , or —OC(═O)N(R B3a ) 2 , wherein each instance of R B3a 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 B3a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
q is 0, 1, 2, or 3;
R C3 is 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, or an oxygen protecting group;
R D3 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 D3a , —N(R D3a ) 2 , —SR D3a , —CN, —SCN, —C(═NR D3a )R D3a , —C(═NR D3a )OR D3a , —C(═NR D3a )N(R D3a ) 2 , —C(═O)R D3a , —C(═O)OR D3a , —C(═O)N(R D3a ) 2 , —NO 2 , —NR D3a C(═O)R D3a , —NR D3a C(═O)OR D3a , —NR D3a C(═O)N(R D3a ) 2 , —OC(═O)R D3a , —OC(═O)OR D3a , or —OC(═O)N(R D3a ) 2 , wherein each instance of R D3a 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 D3a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
Ring A is substituted or unsubstituted, 5- to 6-membered, monocyclic, heterocyclic or heteroaryl ring;
each instance of R J3 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubslituled carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR J3a , —N(R J3a ) 2 , —SR J3a , —CN, —SCN, —C(═NR J3a )R J3a , —C(═NR J3a )OR J3a , —C(═NR J3a )N(R J3a ) 2 , —C(═O)R J3a , —C(═O)OR J3a , —C(═O)N(R J3a ) 2 , NO 2 , —NR J3a C(═O)R J3a , NR J3a C(═O)OR J3a , —NR J3a C(═O)N(R J3a ) 2 , —OC(═O)R J3a , —OC(═O)OR J3a , —OC(═O)N(R J3a ) 2 , or a nitrogen protecting group when attached to a nitrogen atom, wherein each instance of R J3a 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 J3a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
r is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
R F3 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;
R G3 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; and
R H3 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
or R G3 and R H3 are joined to form a substituted or unsubstituted phenyl ring.
36 . The method of claim 35 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
37 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XIII):
or pharmaceutically acceptable salt thereof, wherein:
A is ═N— or ═C(R B4 )—;
A 1 is —N(R 4 )— or —C(R 4 ) 2 —;
R 1 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 2 and R 3 are each 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, —C(═O)R D1 , —C(═O)OR D1 , —C(═O)N(R D1 ) 2 , or a nitrogen protecting group, wherein each instance of R D1 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 D1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring, or a nitrogen protecting group when attached to a nitrogen atom;
R 4 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, —C(═O)R D1 , —C(═O)OR D1 , or —C(═O)N(R D1 ) 2 , wherein each instance of R D1 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 D1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring, or a nitrogen protecting group when attached to a nitrogen atom;
each instance of R B1 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 B1a , —N(R B1a ) 2 , —SR B1a , —CN, —SCN, —C(═NR B1a )R B1a , —C(═NR B1a )OR B1a , —C(═NR B1a )N(R B1a ) 2 , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)N(R B1a ) 2 , —NO 2 , —NR B1a C(═O)R B1a , —NR B1a C(═O)OR B1a , —NR B1a C(═O)N(R B1a ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , or —OC(═O)N(R B1a ) 2 , wherein each instance of R B1a 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 B1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R B2 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 B2a , —N(R B2a ) 2 , —SR B2a , —CN, —SCN, —C(═NR B2a )R B2a , —C(═NR B2a )OR B2a , —C(═NR B2a )N(R B2a ) 2 , —C(═O)R B2a , —C(═O)OR B2a , —C(═O)N(R B2a ) 2 , —NO 2 , —NR B2a C(═O)R B2a , —NR B2a C(═O)OR B2a , —NR B2a C(═O)N(R B2a ) 2 , —OC(═O)R B2a , —OC(═O)OR B2a , or —OC(═O)N(R B2a ) 2 , wherein each instance of R B2a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubslituled 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 B2a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R B3 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubslituled carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR B3a , —N(R B3a ) 2 , —SR B3a , —CN, —SCN, —C(═NR B3a )R B3a , —C(═NR B3a )OR B3a , —C(═NR B3a )N(R B3a ) 2 , —C(═O)R B3a , —C(═O)OR B3a , —C(═O)N(R B3a ) 2 , —NO 2 , —NR B3a C(═O)R B3a , —NR B3a C(═O)OR B3a , —NR B3a C(═O)N(R B3a ) 2 , —OC(═O)R B3a , —OC(═O)OR B3a , or —OC(═O)N(R B3a ) 2 , wherein each instance of R B3a 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 B3a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R B4 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 B4a , —N(R B4a ) 2 , —SR B4a , —CN, —SCN, —C(═NR B4a )R B4a , —C(═NR B4a )OR B4a , —C(═NR B4a )N(R B4a ) 2 , —C(═O)R B4a , —C(═O)OR B4a , —C(═O)N(R B4a ) 2 , —NO 2 , —NR B4a C(═O)R B4a , —NR B4a C(═O)OR B4a , —NR B4a C(═O)N(R B4a ) 2 , —OC(═O)R B4a , —OC(═O)OR B4a , or —OC(═O)N(R B4a ) 2 , wherein each instance of R B4a 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 B4a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
m is 0 or an integer between 1 and 8, inclusive;
p is 0 or an integer between 1 and 4, inclusive;
each of L 1 and L 2 is independently a bond,
each instance of R a1 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; or, if L 1 is
then R a1 of L 1 and one instance of R B1 that is ortho to L 1 are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; and
each instance of R c1 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 c1a , —N(R c1a ) 2 , —SR c1a , —CN, —C(═O)R c1a , —C(═O)OR c1a , —C(═O)N(R c1a ) 2 , —NR c1a C(═O)R c1a , —NR c1a C(═O)OR c1a , —NR c1a C(═O)N(R c1a ) 2 , —OC(═O)R c1a , or —OC(═O)N(R c1a ) 2 , wherein each instance of R c1a 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 c1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
38 . The method of claim 37 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
39 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XIV):
or pharmaceutically acceptable salt thereof, wherein:
R 1 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 when attached to a nitrogen atom;
R 2 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 D1 , —N(R D1 ) 2 , —SR D1 , —CN, —SCN, —C(═NR D1 )R D1 , —C(═NR D1 )OR D1 , —C(═NR D1 )N(R D1 ) 2 , —C(═O)R D1 , —C(═O)OR D1 , —C(═O)N(R D1 ) 2 , —NO 2 , —NR D1 C(═O)R D1 , —NR D1 C(═O)OR D1 , —NR D1 C(═O)N(R D1 ) 2 , —OC(═O)R D1 , —OC(═O)OR D1 , or —OC(═O)N(R D1 ) 2 , wherein each instance of R D1 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 D1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R 3 and R 4 are each 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; or R 3 and R 4 groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R 5 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 unsubslituled aryl, or substituted or unsubstituted heteroaryl;
each instance of R 6 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 B1a , —N(R B1a ) 2 , —SR B1a , —CN, —SCN, —C(═NR B1a )R B1a , —C(═NR B1a )OR B1a , —C(═NR B1a )N(R B1a ) 2 , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)N(R B1a ) 2 , —NO 2 , —NR B1a C(═O)R B1a , —NR B1a C(═O)OR B1a , —NR B1a C(═O)N(R B1a ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , or —OC(═O)N(R B1a ) 2 ;
q is 0, 1, 2, 3, or 4;
A is ═N— or ═C(R 2 )—;
each instance of R B1 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 B1a , —N(R B1a ) 2 , —SR B1a , —CN, —SCN, —C(═NR B1a )R B1a , —C(═NR B1a )OR B1a , —C(═NR B1a )N(R B1a ) 2 , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)N(R B1a ) 2 , —NO 2 , —NR B1a C(═O)R B1a , —NR B1a C(═O)OR B1a , —NR B1a C(═O)N(R B1a ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , or —OC(═O)N(R B1a ) 2 ;
each instance of R B1a 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 B1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
p is 0 or an integer between 1 and 4, inclusive;
n is 0, 1, 2, 3, 4, 5, or 6;
L 1 , L 2 , and L 4 are each independently a bond,
L 3 is
R a1 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 c1 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 c1a , —N(R c1a ) 2 , —SR c1a , —CN, —C(═O)R c1a , —C(═O)OR c1a , —C(═O)N(R c1a ) 2 , —NR c1a C(═O)R c1a , —NR c1a C(═O)OR c1a , —NR c1a C(═O)N(R c1a ) 2 , —OC(═O)R c1a , or —OC(═O)N(R c1a ) 2 , wherein each instance of R c1a 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 c1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
40 . The method of claim 39 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
41 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XV):
or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
W is C(═O)OR Z1 , —C(═O)N(R Z1 ) 2 , —S(═O)OR Z1 , —S(═O)N(R Z1 ) 2 , —S(═O) 2 OR Z1 , —S(═O) 2 N(R Z1 ) 2 , or
Z is —O—, —N(R Z )— or —C(R Z ) 2 —, wherein each instance of R Z is independently 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, —OR Z1 , —SR Z1 , —N(R Z1 ) 2 , or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R Z are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;
each instance of R Z1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R Z1 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R A 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 A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , or —OC(═O)N(R A1 ) 2 , wherein each instance of R A1 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 A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
X is absent, —C(═O)—, or —C(R X ) 2 —, wherein each instance of R X is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R B 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 B1 , —N(R B1 ) 2 , —SR B1 , —CN, —SCN, —C(═NR B1 )R B1 , —C(═NR B1 )OR B1 , —C(═NR B1 )N(R B1 ) 2 , —C(═O)R B1 , —C(═O)OR B1 , —C(═O)N(R B1 ) 2 , —NO 2 , —NR B1 C(═O)R B1 , —NR B1 C(═O)OR B1 , —NR B1 C(═O)N(R B1 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , or —OC(═O)N(R B1 ) 2 , wherein each instance of R B1 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 B1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
m is 0, 1, 2, 3, or 4;
R C is hydrogen or substituted or unsubstituted C 1-6 alkyl;
R D is hydrogen or substituted or unsubstituted alkyl;
R E is hydrogen or substituted or unsubstituted alkyl;
R F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R G is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R H is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or R G and R H are joined to form a substituted or unsubstituted phenyl ring.
42 . The method of claim 41 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
43 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XVI):
or a salt, solvate or hydrate thereof, wherein:
X is N or CR 5 ;
R 5 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
R B is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or C(═O)O R 3 , each of which is optionally substituted;
Ring A is aryl or heteroaryl;
each R A is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or any two R A together with the atoms to which each is attached, form a fused aryl or heteroaryl group;
R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of which is optionally substituted;
R 1 is —(CH 2 ) n -L, wherein n is 0, 1, 2, or 3, and L is H, —C(═O)O—R 3 , —C(═O)—R 3 , —C(═O)—N(R 3 R 4 ), —S(═O) 2 —R 3 , —S(═O) 2 —N(R 3 R 4 ), —N(R 3 R 4 ), —N(R 4 )C(═O)R 3 , optionally substituted aryl, or optionally substituted heteroaryl;
R 2 is H, D, halogen, or optionally substituted alkyl;
each R 3 is independently selected from the group consisting of:
(i) H, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl;
(iii) C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, and N; C 3-12 cycloalkyl, substituted C 3-12 cycloalkyl, C 3-12 cycloalkenyl, or substituted C 3-12 cycloalkenyl, each of which is optionally substituted; and
(iv) —NH 2 , —N═CR 4 R 6 ;
each R 4 is independently H, alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered ring; and
R 6 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
or R 4 and R 6 are taken together with the carbon atom to which they are attached to form a 4- to 10-membered ring;
m is 0, 1, 2, or 3;
provided that:
(a) if Ring A is thienyl, X is N, R is phenyl or substituted phenyl, R 2 is H, R B is methyl, R 1 is —(CH 2 ) n -L, n is 1, and L is —C(═O)—N(R 3 R 4 ), then R 3 and R 4 are not taken together with the nitrogen atom to which they are attached to form a morpholino ring;
(b) if Ring A is thienyl, X is N, R is substituted phenyl, R 2 is H, R B is methyl, R 1 is (CH 2 ) n -L, n is 1, L is —C(═O)—N(R 3 R 4 ), and one of R 3 and R 4 is H, then the other of R 3 and R 4 is not methyl, hydroxyethyl, alkoxy, phenyl, substituted phenyl, pyridyl or substituted pyridyl; and
(c) if Ring A is thienyl, X is N, R is substituted phenyl, R 2 is H, R B is methyl, R 1 is —(CH 2 ) n -L, n is 1, and L is —C(═O)O—R 3 , then R 3 is not methyl or ethyl.
44 . The method of claim 43 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
45 . The method of claim 43 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
46 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XVII):
or a pharmaceutically acceptable salt thereof, wherein:
R A is 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, or substituted or unsubstituted heteroaryl;
R B is 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, or substituted or unsubstituted heteroaryl;
or R A and R B are joined to form a substituted or unsubstituted, carbocyclic ring, or a substituted or unsubstituted, heterocyclic ring;
R C is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
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 ;
each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubslituled 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 ring, or a substituted or unsubstituted, heteroaryl ring;
m is 0, 1, 2, 3, or 4;
X is —O—, —S—, —N(R X1 )—, or —C(R X2 ) 2 —, wherein R X1 is hydrogen, substituted or unsubslituled C 1-6 alkyl, or a nitrogen protecting group, and wherein each instance of R X2 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
R E 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 F is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R G is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, or a nitrogen protecting group;
each instance of R H 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
n is 0, 1, 2, 3, or 4.
47 . The method of claim 46 , wherein the transcription inhibitor is of the formula:
wherein R A is
or a pharmaceutically acceptable salt thereof.
48 . The method of claim 46 , wherein the transcription inhibitor is of the formula:
R A
R B
or a pharmaceutically acceptable salt thereof.
49 . The method of claim 46 , wherein the transcription inhibitor is of the formula:
wherein
or a pharmaceutically acceptable salt thereof.
50 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is of Formula (XVIII):
or pharmaceutically acceptable salt thereof, wherein:
R A is 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, or substituted or unsubstituted heteroaryl;
R B is 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, or substituted or unsubstituted heteroaryl;
or R A and R B are joined to form a substituted or unsubstituted, carbocyclic ring, or a substituted or unsubstituted, heterocyclic ring;
R C is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R 1 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 2 and R 3 are each 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, —C(═O)R D1 , —C(═O)OR D1 , —C(═O)N(R D1 ) 2 , or a nitrogen protecting group, wherein each instance of R D1 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 D1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring, or a nitrogen protecting group when attached to a nitrogen atom;
each instance of R B1 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 B1a , —N(R B1a ) 2 , —SR B1a , —CN, —SCN, —C(═NR B1a )R B1a , —C(═NR B1a )OR B1a , —C(═NR B1a )N(R B1a ) 2 , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)N(R B1a ) 2 , —NO 2 , —NR B1a C(═O)R B1a , —NR B1a C(═O)OR B1a , —NR B1a C(═O)N(R B1a ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , or —OC(═O)N(R B1a ) 2 , wherein each instance of R B1a 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 B1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R B3 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 B3a , —N(R B3a ) 2 , —SR B3a , —CN, —SCN, —C(═NR B3a )R B3a , —C(═NR B3a )OR B3a , —C(═NR B3a )N(R B3a ) 2 , —C(═O)R B3a , —C(═O)OR B3a , —C(═O)N(R B3a ) 2 , —NO 2 , —NR B3a C(═O)R B3a , —NR B3a C(═O)OR B3a , —NR B3a C(═O)N(R B3a ) 2 , —OC(═O)R B3a , —OC(═O)OR B3a , or —OC(═O)N(R B3a ) 2 , wherein each instance of R B3a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubslituled 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 B3a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
p is 0 or an integer between 1 and 4, inclusive;
L is a bond,
R a1 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 c1 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 c1a , —N(R c1a ) 2 , —SR c1a , —CN, —C(═O)R c1a , —C(═O)OR c1a , —C(═O)N(R c1a ) 2 , —NR c1a C(═O)R c1a , —NR c1a C(═O)OR c1a , —NR c1a C(═O)N(R c1a ) 2 , —OC(═O)R c1a , or —OC(═O)N(R c1a ) 2 , wherein each instance of R c1a 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 c1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
51 . The method of claim 50 , wherein the transcription inhibitor is of the formula:
wherein R A is
or a pharmaceutically acceptable salt thereof.
52 . The method of claim 50 , wherein the transcription inhibitor is of the formula:
R A or R B
R B or R A
or a pharmaceutically acceptable salt thereof.
53 . The method of claim 50 , wherein the transcription inhibitor is of the formula:
wherein
or a pharmaceutically acceptable salt thereof.
54 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is dinaciclib, DCA, palbociclib, or a pharmaceutically acceptable salt thereof.
55 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is AT7519M, P1446A-05, AG-024322, (R)-roscovitine, P276-00, SNS-032, LEE011, PD 0332991, GT28-01, NSC 638850, aminopurvalanol A, arcyriaflavin A, AZD 5438, (R)-CR8, (R)-DRF053, dihydrochloride, flavopiridol, 10Z-hymenialdisine, irdirubin-3′-oxime, kenpaullone, NSC 625987, NSC 663284, NSC 693868, NU 2058, NU 6140, olomoucine, PHA 767491, purvalanol A, purvalanol B, RO 3306, ryuvidine, senexin A, SNS 032, SU 9516, or a pharmaceutically acceptable salt thereof.
56 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is p 16 protein, p15 protein, p18 protein, p19 protein, p21/WAF1 protein, p27 protein, or p57 protein.
57 . The method of any one of claims 1 - 5 , wherein the transcription inhibitor is I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, RVX-208, LY294002, BMS-986158, GSK525762, or a pharmaceutically acceptable salt thereof.
58 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor.
59 . The method of claim 58 , wherein the RTK inhibitor is afatinib, axitinib, cediranib, erlotinib, gefitinib, grandinin, imatinib, lapatinib, lestaurtinib, neratinib, pazopanib, quizartinib, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, vandetanib, or a pharmaceutically acceptable salt thereof.
60 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is a fibroblast growth factor receptor (FGER) inhibitor.
61 . The method of claim 60 , wherein the FGER inhibitor is BGJ398, or a pharmaceutically acceptable salt thereof.
62 . The method of claim 60 , wherein the FGFR inhibitor is PD173074, pazopanib, masatinib, dovitinib, ponatinib, regorafenib, pirfenidone, nintedanib, brivanib, lenvatinib, cediranib, AZD4547, SU6668, BGJ398, ENMD2076, picropodophyllin, RG1507, dalotuzumab, figitumumab, cixutumumab, BIIB022, AMG479, FP1039, IMCA1, PRO001, R3Mab, MK-2461, SSR128129E, tyrphostin AG 1296, CH5183284, LY2874455, JNJ-42756493, lucitanib, orantinib, danusertib, or a pharmaceutically acceptable salt thereof.
63 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is an epidermal growth factor receptor (EGFR) inhibitor.
64 . The method of claim 63 , wherein the EGFR inhibitor is erlotinib, lapatinib, AZD8931, WZ4002, or a pharmaceutically acceptable salt thereof.
65 . The method of claim 63 , wherein the EGFR inhibitor is panitumumab, vandetanib, icotinib, afatinib, brigatinib, CO-1688, AZD-4769, poziotinib, CUDC-101, S-222611, AC-480, imgatuzumab, sapitinib, TAS-2913, theiiatinib, XGFR-2421, HM-61713B, epitinib, NRC-2694, MLBS-42, JRP-890, cetuximab, AL-6802, TAK-285, BGB-102, AEE788, gefitinib, DMS-3008, TX-2036, KI-6783, KI-6896, or a pharmaceutically acceptable salt thereof.
66 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is a mitogen-activated protein kinase (MEK) inhibitor.
67 . The method of claim 66 , wherein the MEK inhibitor is trametinib or vemurafenib, or a pharmaceutically acceptable salt thereof.
68 . The method of claim 66 , wherein the MEK inhibitor is selumetinib, MEK162, PD325901, PD98059, XL518, C 1-10 40, antroquinonol, AS-1940477, AS-703988, BI-847325, E-6201, GDC-0623, GDC-0973, RG422, R04987655, R05126766, SL327, WX-554, U0126, BAY869766, vemurafenib, TAK-733, pimasertib, binimetinib, YopJ polypeptide, or a pharmaceutically acceptable salt thereof.
69 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor.
70 . The method of claim 69 , wherein the PI3K inhibitor is BKM120, BEZ235, or a pharmaceutically acceptable salt thereof.
71 . The method of claim 69 , wherein the PI3K inhibitor is GDC0941, tozasertib, GSK1059615, PX866, LY294002, SF1126, XL147, XL765, BGT226, BYL719, BAY80946, BAY841236, GDC-0941, GDC-0032, GDC-0980, GDC-0941, PX-866, GSK2126458, CAL-101, INK 1117, ZSTK474, PWT33597, AEZS-136, PKI-587, PE-4691502, PE-05212384, wortmannin, demethoxyviridin, pictilisib, idelalisib, IPI-145, or a pharmaceutically acceptable salt thereof.
72 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is a receptor tyrosine-protein kinase erbB-2 (HER2) inhibitor.
73 . The method of claim 72 , wherein the HER2 inhibitor is lapatinib, or a pharmaceutically acceptable salt thereof.
74 . The method of claim 72 , wherein the HER2 inhibitor is trastuzumab, ado-trastuzumab emtansine, pertuzumab, neratinib, BMS690514, BIBW-2992, BMS 599626, canertinib, XL647, ertumaxomab, gefitinib, erlotinib, pelitinib, CP-654577, CP-724714, HKI-272, neratinib, PKI166, AEE788, BMS-599626, HKI-727, HKI-357, BIBW 2992, AG1478, ARRY-380, ARRY-334543, BAY846, D69491, DXL-702, JNJ-26483327, or a pharmaceutically acceptable salt thereof.
75 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is a mammalian target of rapamycin (mTOR) inhibitor.
76 . The method of claim 75 , wherein the mTOR inhibitor is Torin2, or a pharmaceutically acceptable salt thereof.
77 . The method of claim 75 , wherein the mTOR inhibitor is GDC-0980, OSI-027, AZD8055, INK-128, sirolimus, temsirolimus, everolimus, ridaforolimus, AP23573, rapamycin, simapimod, AZD8055, PF04691502, deforolimus, intercellular protein FKBP38, wortmannin, SF1126, or a pharmaceutically acceptable salt thereof.
78 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is an anaplastic lymphoma kinase (ALK) inhibitor.
79 . The method of claim 78 , wherein the ALK inhibitor is crizotinib, AP26113, LDK378, TAE-684, CEP-14083, CEP-14513, CEP-11988, WHI-P131, ceritinib, alectinib, staurosporine, CH5424802 (RO5424802), ASP3026, TSR-011, X-396, WHI-P154, or a pharmaceutically acceptable salt thereof.
80 . The method of any one of claims 1 - 57 , wherein the kinase inhibitor is an inhibitor of AAK1, ABE, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARC, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC, AXE, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1, CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3, CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK5ps, CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2, CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1, CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L, CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1, DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EphA1, EphA10, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB6, Erk1, Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3, Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGR, FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK, GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRKbps, GPRK7, GSK3A, GSK3B, Haspin, HCK, ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKc, ILK, INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT, KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1, LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8, MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3, MARK4, MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07, MARKps08, MARKps09, MARKps10, MARKps11, MARKps12, MARKps13, MARKps15, MARKps10, MARKps17, MARKps18, MARKps19, MARKps20, MARKps21, MARKps22, MARKps23, MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29, MARKps30, MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET, MISR2, MLK1, MLK2, MLK3, MLK4, MLKL, MNK1, MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa, MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3, MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK2ps1, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7, NEK8, NEK9, NIK, NIM1, NEK, NRBP1, NRBP2, NuaK1, NuaK2, Obscn, Obscn2, OSR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2, PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1, PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2, PHKg1, PHKg1ps1, PHKg1ps2, PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3, PINK1, PITSLRE, PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR, PLK1, PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4, PRP4ps, PRPK, PSKH1, PSKHlps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps, RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288, SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK (e.g., SIK1, SIK2), skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1, SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1, STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2, VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1/HGK, ZC2/TNIK, ZC3/MINK, ZC4/NRK, or a combination thereof.
81 . The method of any one of claims 1 - 80 , wherein the molar ratio of the transcription inhibitor to the kinase inhibitor is between 0.00001:1 and 100:1, inclusive.
82 . The method of claim 81 , wherein the molar ratio of the transcription inhibitor to the kinase inhibitor is between 0.001:1 and 1:1, inclusive.
83 . The method of any one of claims 1 - 82 , wherein the proliferative disease is cancer.
84 . The method of claim 83 , wherein the cancer is bladder cancer, lung cancer, esophageal cancer, skin cancer, or throat cancer.
85 . The method of claim 82 or 83 , wherein the cancer is associated with a mutation in an epidermal growth factor receptor (EGFR) gene.
86 . The method of claim 85 , wherein the mutation is a T790M mutation, L858R mutation, or exon 19 deletion mutation.
87 . The method of any one of claims 83 - 86 , wherein the cancer is associated with fibroblast growth factor-2 (FGF2)-fibroblast growth factor receptor 1 (FGFR1) activation through amplification, FGFR3-TACC3 fusion, EMF4-AFK fusion, HER2 amplification, or KRAS codons 12, 13 or 61 mutations.
88 . The method of any one of claims 83 - 87 , wherein the cancer is associated with a mutation in neuroblastoma RAS viral oncogene homolog (NRAS).
89 . The method of claim 88 , wherein the mutation is a Q61R mutation.
90 . The method of claim any one of claims 83 - 89 , wherein the cancer is associated with mesenchymal-epithelial transition (MET) amplification.
91 . The method of claim any one of claims 83 - 90 , wherein the cancer is associated with feedback activation of signal transducer and activator of transcription 3 (STAT3).
92 . The method of any one of claims 1 - 82 , wherein the proliferative disease is a benign neoplasm.
93 . The method of any one of claims 1 - 82 , wherein the proliferative disease is associated with pathological angiogenesis.
94 . The method of any one of claims 1 - 82 , wherein the proliferative disease is an inflammatory disease.
95 . The method of any one of claims 1 - 82 , wherein the proliferative disease is an autoimmune disease.
96 . The method of any one of claims 1 - 95 , wherein the subject is a human.
97 . A pharmaceutical composition comprising:
a transcription inhibitor recited in any one of claims 6 - 57 ; a kinase inhibitor recited in any one of claims 58 - 80 ; and optionally a pharmaceutically acceptable excipient; wherein the transcription inhibitor and the kinase inhibitor are not the same.
98 . The pharmaceutical composition of claim 97 further comprising an additional pharmaceutical agent, wherein the additional pharmaceutical agent is not the same as the transcription inhibitor and is not the same as the kinase inhibitor.
99 . A kit comprising:
a transcription inhibitor recited in any one of claims 6 - 57 ; a kinase inhibitor recited in any one of claims 58 - 80 ; and instructions for using the transcription inhibitor and the kinase inhibitor; wherein the transcription inhibitor and the kinase inhibitor are not the same.
100 . A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of:
a transcription inhibitor; and radiation therapy.
101 . The method of claim 100 , wherein the transcription inhibitor and radiation therapy are synergistic in treating the proliferative disease, compared to the transcription inhibitor alone or radiation therapy alone.
102 . The method of claims 100 or 101 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
103 . The method of any one of claims 100 or 101 , wherein the transcription inhibitor is of the formula:
or a pharmaceutically acceptable salt thereof.
104 . The method of any one of claims 100 - 103 , wherein the proliferative disease is cancer.
105 . The method of claim 104 , wherein the proliferative disease is a cancer of the head, neck, or throat.
106 . The method of claim 105 , wherein the proliferative disease is head and neck cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, lip cancer, oral cavity cancer, oropharyngeal cancer, paranasal sinus cancer, nasal cavity cancer, salivary gland cancer, thyroid cancer, or parathyroid cancer.Join the waitlist — get patent alerts
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