# US 2017/0280720 A1 · Arginine methyltransferase inhibitors and uses thereof

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- Number: US 2017/0280720 A1
- Document ID: US20170280720A1
- Status: Published application
- Kind: A1
- Application number: 15/511,514
- Filed: 2015-09-17
- Published: 2017-10-05
- Earliest claimed: 2014-09-17
- Assignees: Epizyme, Inc.
- Applicants: Epizyme, Inc.
- Inventors: Richard CHESWORTH; Lorna Helen MITCHELL; Gideon SHAPIRO; Oscar Miguel MORADEI; Kevin Wayne KUNTZ; Kenneth W. DUNCAN; Lei JIN
- Web page: https://patentgrep.com/patent/US20170280720A1

## CPC

- A01N 47/10: Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
- C07D 209/10: with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D 233/54: having two double bonds between ring members or between ring members and non-ring members
- C07D 241/02: not condensed with other rings
- C07D 277/20: having two or three double bonds between ring members or between ring members and non-ring members
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- A61K 38/45: Transferases (2)
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is optionally substituted aryl, optionally substituted pyridinyl, optionally substituted bicyclic heteroaryl with one, three, or four nitrogen ring atoms, optionally substituted indazolyl, optionally substituted azaindolyl, or optionally substituted benzoimidazolyl;
m is 0, 1, 2, 3, or 4;
Rx is optionally substituted C1-4 alkyl or optionally substituted C3-4 cycloalkyl; and
each of R3a and R3b is independently hydrogen, optionally substituted C1-4 alkyl, or optionally substituted C3-4 cycloalkyl;
each instance of R1 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2;
each instance of RA is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group; and
each instance of RB is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
or two RB taken together with the intervening nitrogen form optionally substituted heterocyclyl;
or RA and RB taken together with the intervening atoms form optionally substituted heterocyclyl; and
provided that the optional substituent on Ring A is not an optionally substituted pyridone.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (I-a):

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (I-al):
or a pharmaceutically acceptable salt thereof; wherein each instance of R1a and R1b is independently hydrogen, halogen, or optionally substituted C1-6 alkyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R1a is hydrogen.

### Claim 5 (depends on 3)

The compound of claim 3, wherein R1a is halogen.

### Claim 6 (depends on 3)

The compound of claim 3, wherein R1a is F.

### Claim 7 (depends on 3)

The compound of claim 3, wherein R1a is unsubstituted C1-6 alkyl.

### Claim 8 (depends on 3)

The compound of claim 3, wherein R1a is methyl.

### Claim 9 (depends on 3, 4, 5, 6, 7, 8)

The compound of any one of claims 3-8, wherein R1b is hydrogen.

### Claim 10 (depends on 3, 4, 5, 6, 7, 8)

The compound of any one of claims 3-8, wherein R1b is halogen.

### Claim 11 (depends on 10)

The compound of any one of claim 10, wherein R1b is F.

### Claim 12 (depends on 3, 4, 5, 6, 7, 8)

The compound of any one of claims 3-8, wherein R1b is unsubstituted C1-6 alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R1b is methyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (I-b):
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The compound of claim 14, wherein m is 0.

### Claim 16 (depends on 14)

The compound of claim 14, wherein m is 1.

### Claim 17 (depends on 14, 16)

The compound of claim 14 or 16, wherein R1 is hydrogen.

### Claim 18 (depends on 14, 16)

The compound of claim 14 or 16, wherein R1 is unsubstituted C1-6 alkyl.

### Claim 19 (depends on 18)

The compound of claim 18, wherein R1 is methyl.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein Ring A is an optionally substituted aryl.

### Claim 21 (depends on 20)

The compound of claim 20, wherein Ring A is optionally substituted phenyl of Formula (A-1):
wherein each of R2a, R2b, R2c, R2d, and R2e is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2.

### Claim 22 (depends on 21)

The compound of claim 21, wherein Ring A is of one of the following formulae:

### Claim 23 (depends on 21, 22)

The compound of any one of claims 21-22, wherein R2b is —N(RB)2 or —C(═O)N(RB)2.

### Claim 24 (depends on 21, 22, 23)

The compound of any one of claims 21-23, wherein R2b is —N(RB)2; and each instance of RB is independently hydrogen or optionally substituted alkyl.

### Claim 25 (depends on 21, 22, 23, 24)

The compound of any one of claims 21-24, wherein R2b is —N(CH3)RB, wherein RB is hydrogen or optionally substituted alkyl.

### Claim 26 (depends on 25)

The compound of claim 25, wherein RB is —CH2-cyclopropyl.

### Claim 27 (depends on 23)

The compound of claim 23, wherein R2b is —C(═O)N(RB)2, wherein each instance of RB is independently hydrogen, optionally substituted alkyl, or optionally substituted heterocyclyl.

### Claim 28 (depends on 27)

The compound of claim 27, wherein R2b is —C(═O)NHRB.

### Claim 29 (depends on 28)

The compound of claim 28, wherein RB is tetrahydropyranyl.

### Claim 30 (depends on 28)

The compound of claim 28, wherein RB is substituted alkyl.

### Claim 31 (depends on 30)

The compound of claim 30, wherein RB is —C1-6alkyl-heterocyclyl.

### Claim 32 (depends on 31)

The compound of claim 31, wherein RB is —CH2-tetrahydropyranyl.

### Claim 33 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The compound of any one of claims 21-32, wherein R2c is optionally substituted alkyl or —C(═O)N(RB)2.

### Claim 34 (depends on 33)

The compound of claim 33, wherein R2c is unsubstituted C1-6 alkyl.

### Claim 35 (depends on 34)

The compound of claim 34, wherein R2c is methyl.

### Claim 36 (depends on 33)

The compound of claim 33, wherein R2c is —C(═O)N(RB)2; and each instance of RB is independently hydrogen, optionally substituted alkyl, or optionally substituted heterocyclyl.

### Claim 37 (depends on 36)

The compound of claim 36, wherein R2c is —C(═O)NHRB; and RB is optionally substituted C1-6 alkyl or optionally substituted heterocyclyl.

### Claim 38 (depends on 37)

The compound of claim 37, wherein RB is substituted C1-6 alkyl.

### Claim 39 (depends on 38)

The compound of claim 38, wherein RB is —CH2-tetrahydropyranyl.

### Claim 40 (depends on 37)

The compound of claim 37, wherein RB is unsubstituted C1-6 alkyl.

### Claim 41 (depends on 40)

The compound of claim 40, wherein RB is methyl.

### Claim 42 (depends on 37)

The compound of claim 37, wherein RB is unsubstituted heterocyclyl.

### Claim 43 (depends on 42)

The compound of claim 42, wherein RB is tetrahydropyranyl.

### Claim 44 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The compound of any one of claims 21-43, wherein R2d is —N(RB)2 or —C(═O)N(RB)2.

### Claim 45 (depends on 44)

The compound of claim 44, wherein R2d is —N(RB)2; and each instance of RB is independently hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl.

### Claim 46 (depends on 45)

The compound of claim 45, wherein R2d is —N(CH3)RB or —N(C2H5)RB.

### Claim 47 (depends on 46)

The compound of claim 46, wherein RB is substituted alkyl.

### Claim 48 (depends on 46)

The compound of claim 46, wherein RB is —C1-4alkyl-carbocyclyl.

### Claim 49 (depends on 46)

The compound of claim 46, wherein RB is —CH2-cyclopropyl.

### Claim 50 (depends on 46)

The compound of claim 46, wherein RB is optionally substituted heterocyclyl.

### Claim 51 (depends on 46)

The compound of claim 46, wherein RB is tetrahydropyranyl.

### Claim 52 (depends on 44)

The compound of claim 44, wherein R2d is —C(═O)N(RB)2; and each instance of RB is independently hydrogen, optionally substituted alkyl, or optionally substituted heterocyclyl.

### Claim 53 (depends on 48)

The compound of claim 48, wherein RB is substituted alkyl.

### Claim 54 (depends on 53)

The compound of claim 53, wherein RB is —C1-4alkyl-heterocyclyl.

### Claim 55 (depends on 54)

The compound of claim 54, wherein RB is —CH2-tetrahydropyranyl.

### Claim 56 (depends on 52)

The compound of claim 52, wherein RB is unsubstituted heterocyclyl.

### Claim 57 (depends on 56)

The compound of claim 56, wherein RB is tetrahydropyranyl.

### Claim 58 (depends on 44)

The compound of claim 44, wherein two RB taken together with the intervening nitrogen form optionally substituted heterocyclyl.

### Claim 59 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The compound of any one of claims 21-58, wherein each of R2b, R2c, and R2d is independently of one of the following formulae:

### Claim 60 (depends on 22)

The compound of claim 22, wherein Ring A is of the formula:
wherein each of RN2a and RN2b is independently hydrogen, optionally substituted alkyl, or optionally substituted aryl.

### Claim 61 (depends on 60)

The compound of claim 60, wherein RN2a is hydrogen.

### Claim 62 (depends on 60, 61)

RN2b The compound of any one of claims 60-61, wherein R is optionally substituted phenyl.

### Claim 63 (depends on 62)

The compound of claim 62, wherein Ring A is of the formula:

### Claim 64 (depends on 22)

The compound of claim 22, wherein Ring A is of the formula:
wherein RN2c is optionally substituted alkyl.

### Claim 65 (depends on 64)

The compound of claim 64, wherein RN2C is unsubstituted C1-6 alkyl.

### Claim 66 (depends on 65)

The compound of any one of claims 65, wherein RN2C is methyl or ethyl.

### Claim 67 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein Ring A is of Formula (A-3)
wherein:
each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2; and
p is 0, 1, 2, or 3;
or RB and another R4 taken together with the intervening atoms form optionally substituted heterocyclyl.

### Claim 68 (depends on 67)

The compound of claim 67, wherein p is 1.

### Claim 69 (depends on 67)

The compound of claim 67, wherein p is 2.

### Claim 70 (depends on 67)

The compound of claim 67, wherein Ring A is of one of the following formulae:
wherein:
R4a is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2.

### Claim 71 (depends on 70)

The compound of claim 70, wherein each instance of R4 and R4a is independently hydrogen, optionally substituted C1-6 alkyl, —ORA, —NRBC(═O)RA, or —C(═O)N(RB)2.

### Claim 72 (depends on 71)

The compound of claim 71, wherein RB is hydrogen or optionally substituted alkyl.

### Claim 73 (depends on 70)

The compound of claim 70, wherein R4 and R4a is independently hydrogen, optionally substituted C1-6 alkyl, —ORA, —NHC(═O)RA, —C(═O)NHRB, or —C(═O)N(CH3)RB.

### Claim 74 (depends on 73)

The compound of claim 73, wherein RA is hydrogen or optionally substituted alkyl; and RB is optionally substituted —C1-4alkyl-heteroaryl or optionally substituted —C1-4alkyl-phenyl.

### Claim 75 (depends on 67, 68, 69, 70, 71, 72, 73, 74)

The compound of any one of claims 67-74, wherein RA and RB taken together with the intervening atoms form optionally substituted heterocyclyl.

### Claim 76 (depends on 67, 68, 69, 70, 71, 72, 73, 74)

The compound of any one of claims 67-74, wherein RB and another R4 taken together with the intervening atoms form optionally substituted heterocyclyl.

### Claim 77 (depends on 67, 68, 69, 70, 71, 72, 73, 74, 75, 76)

The compound of any one of claims 67-76, wherein Ring A is one of the following formulae:

### Claim 78 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein Ring A is of Formula (A-4):
wherein:
each instance of R5 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2;
q is 0, 1, 2, 3, 4, or 5; and
each instance of RN4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
or RB and another R5 taken together with the intervening atoms form optionally substituted heterocyclyl.

### Claim 79 (depends on 78)

The compound of claim 78, wherein Ring A is of Formula (A-4a):

### Claim 80 (depends on 79)

The compound of claim 79, wherein R5 is optionally substituted C1-6 alkyl.

### Claim 81 (depends on 80)

The compound of claim 80, wherein R5 is unsubstituted C1-6 alkyl.

### Claim 82 (depends on 82)

The compound of claim 82, wherein R5 is methyl.

### Claim 83 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein Ring A is one of the following formulae:
wherein:
each instance of R6 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2; and
s is 0, 1, 2, 3, or 4;
each instance of RN5 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

### Claim 84 (depends on 83)

The compound of claim 83, wherein s is 1.

### Claim 85 (depends on 83)

The compound of claim 83, wherein s is 2.

### Claim 86 (depends on 83, 84, 85)

The compound of any one of claims 83-85, wherein Ring A is of one of the following formulae:

### Claim 87 (depends on 83, 84, 85, 86)

The compound of any one of claims 83-86, wherein RN5 is hydrogen, optionally substituted alkyl, or —C(═O)NHRB; and RB is hydrogen or optionally substituted alkyl.

### Claim 88 (depends on 87)

The compound of claim 87, wherein RN5 is hydrogen.

### Claim 89 (depends on 87)

The compound of claim 87, wherein RN5 is unsubstituted C1-6 alkyl.

### Claim 90 (depends on 89)

The compound of claim 89, wherein RN5 is isopropyl.

### Claim 91 (depends on 89)

The compound of claim 89, wherein RN5 is substituted alkyl.

### Claim 92 (depends on 91)

The compound of claim 91, wherein RN5 is of Formula (i):
wherein R7 is hydrogen, optionally substituted alkyl, —ORA, —C(═O)RA, or —C(═O)N(RB)2.

### Claim 93 (depends on 92)

The compound of claim 92, wherein:
each instance of RA is independently optionally substituted alkyl, optionally substituted phenyl, or optionally substituted heterocyclyl; and
each instance of RB is independently optionally substituted alkyl;
or two RB taken together with the intervening nitrogen form optionally substituted heterocyclyl.

### Claim 94 (depends on 92, 93)

The compound of claim 92 or 93, wherein RN5 is of one of the following formulae:

### Claim 95 (depends on 91)

The compound of claim 91, wherein RN5 is of Formula (ii):
wherein RN7 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.

### Claim 96 (depends on 95)

The compound of claim 95, wherein RN7 is hydrogen.

### Claim 97 (depends on 95)

The compound of claim 95, wherein RN7 is a nitrogen protecting group.

### Claim 98 (depends on 95)

The compound of claim 95, wherein RN7 is acyl.

### Claim 99 (depends on 95)

The compound of claim 95, wherein RN7 is of one of the following formulae:

### Claim 100 (depends on 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99)

The compound of any one of claims 83-99, wherein R6 is —C(═O)N(RB)2.

### Claim 101 (depends on 100)

The compound of claim 100, wherein each instance of RB is independently hydrogen or optionally substituted alkyl.

### Claim 102 (depends on 101)

The compound of claim 101, wherein R6 is —C(═O)NHRB.

### Claim 103 (depends on 102)

The compound of claim 102, wherein R6 is —C(═O)N(CH3)RB.

### Claim 104 (depends on 100, 101, 102, 103)

The compound of any one of claims 100-103, wherein RB is substituted alkyl.

### Claim 105 (depends on 104)

The compound of claim 104, wherein RB is optionally substituted —C1-6alkyl-phenyl.

### Claim 106 (depends on 105)

The compound of claim 105, wherein RB is of one of the following formulae:

### Claim 107 (depends on 104)

The compound of claim 104, wherein RB is optionally substituted —C1-6alkyl-heteroaryl.

### Claim 108 (depends on 83)

The compound of claim 83, wherein Ring A is of one of the following formulae:

### Claim 109 (depends on 108)

The compound of claim 108, wherein RN5 is hydrogen.

### Claim 110 (depends on 108, 109)

The compound of any one of claims 108-109, wherein R6 is unsubstituted C1-6 alkyl.

### Claim 111 (depends on 110)

The compound of claim 110, wherein R6 is methyl.

### Claim 112 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein Ring A is of one of the following formulae:
wherein:
each instance of RA1 and RA2 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2;
z is 0, 1, 2, or 3;
each instance of RA is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group; and
each instance of RAN and RB is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
or two RB taken together with the intervening nitrogen form optionally substituted heterocyclyl;
or RA and RB taken together with the intervening atoms form optionally substituted heterocyclyl.

### Claim 113 (depends on 112)

The compound of claim 112, wherein RAN is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

### Claim 114 (depends on 113)

The compound of claim 113, wherein RAN is hydrogen.

### Claim 115 (depends on 112, 113)

The compound of any one of claims 112-113, wherein RAN is optionally substituted alkyl.

### Claim 116 (depends on 115)

The compound of claim 115, wherein RAN is unsubstituted alkyl.

### Claim 117 (depends on 116)

The compound of claim 116, wherein RAN is methyl, ethyl, n-propyl, or isopropyl.

### Claim 118 (depends on 117)

The compound of claim 117, wherein RAN is substituted alkyl.

### Claim 119 (depends on 118)

The compound of claim 118, wherein RAN is of Formula
wherein:
h is 0, 1, 2, 3, or 4;
i is 0, 1, 2, 3, 4, or 5; and
each instance of R8 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2.

### Claim 120 (depends on 119)

The compound of claim 119, wherein i is 0.

### Claim 121 (depends on 119)

The compound of claim 119, wherein i is 1.

### Claim 122 (depends on 119)

The compound of claim 119, wherein i is 2.

### Claim 123 (depends on 119, 120, 121, 122)

The compound of any one of claims 119-122, wherein his 1.

### Claim 124 (depends on 119, 120, 121, 122)

The compound of any one of claims 119-122, wherein his 2.

### Claim 125 (depends on 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124)

The compound of claim 112-124, wherein RAN is of one of the following formulae:

### Claim 126 (depends on 119, 120, 121, 122, 123, 124, 125)

The compound of any one of claims 119-125, wherein R8 is CN.

### Claim 127 (depends on 119, 120, 121, 122, 123, 124, 125)

The compound of any one of claims 119-125, wherein R8 is halogen.

### Claim 128 (depends on 127)

The compound of claim 127, wherein R8 is Cl.

### Claim 129 (depends on 119, 120, 121, 122, 123, 124, 125)

The compound of any one of claims 119-125, wherein R8 is unsubstituted alkyl.

### Claim 130 (depends on 129)

The compound of claim 129, wherein R8 is methyl.

### Claim 131 (depends on 119, 120, 121, 122, 123, 124, 125)

The compound of any one of claims 119-125, wherein R8 is —ORA; and RA is optionally substituted alkyl.

### Claim 132 (depends on 131)

The compound of claim 131, wherein R8 is —OCH3.

### Claim 133 (depends on 119, 120, 121, 122, 123, 124, 125)

The compound of any one of claims 119-125, wherein R8 is —SO2RA; and RA is optionally substituted alkyl.

### Claim 134 (depends on 133)

The compound of claim 133, wherein R8 is —SO2CH3.

### Claim 135 (depends on 119, 120, 121, 122, 123, 124, 125)

The compound of any one of claims 119-125, wherein R8 is —C(═O)N(RB)2.

### Claim 136 (depends on 135)

The compound of claim 135, wherein:
each instance of RB is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
or two RB taken together with the intervening nitrogen form optionally substituted heterocyclyl.

### Claim 137 (depends on 135)

The compound of claim 135, wherein R8 is —C(═O)NHRB or —C(═O)N(CH3)RB.

### Claim 138 (depends on 135, 136, 137)

The compound of any one of claims 135-137, wherein RB is hydrogen or optionally substituted alkyl.

### Claim 139 (depends on 138)

The compound of claim 138, wherein RB is unsubstituted alkyl.

### Claim 140 (depends on 139)

The compound of claim 139, wherein RB is methyl.

### Claim 141 (depends on 138)

The compound of claim 138, wherein RB is substituted alkyl.

### Claim 142 (depends on 141)

The compound of claim 141, wherein RB is optionally substituted —C1-4alkyl-alkoxy, optionally substituted —C1-4alkyl-aryl, optionally substituted —C1-4alkyl-heterocyclyl, or optionally substituted —C1-4alkyl-acyl.

### Claim 143 (depends on 142)

The compound of claim 142, wherein RB is of one of the following formulae:

### Claim 144 (depends on 135, 136, 137)

The compound of any one of claims 135-137, wherein RB is optionally substituted carbocyclyl.

### Claim 145 (depends on 144)

The compound of claim 144, wherein RB is cyclopropyl, cyclopentyl, cyclohexyl, or

### Claim 146 (depends on 135, 136, 137)

The compound of any one of claims 135-137, wherein RB is optionally substituted phenyl.

### Claim 147 (depends on 146)

The compound of claim 146, wherein RB is of one of the following formulae:

### Claim 148 (depends on 135, 136, 137)

The compound of any one of claims 135-137, wherein RB is optionally substituted heterocyclyl.

### Claim 149 (depends on 148)

The compound of claim 148, wherein RB is tetrahydropyranyl.

### Claim 150 (depends on 135, 136, 137)

The compound of any one of claims 135-137, wherein two RB taken together with the intervening nitrogen form optionally substituted heterocyclyl.

### Claim 151 (depends on 150)

The compound of claim 150, wherein R8 is one of the following formulae:

### Claim 152 (depends on 118)

The compound of claim 118, wherein RAN is of the formula
wherein:
each instance of j is 0, 1, 2, 3, or 4;
each instance of k is 0, 1, 2, 3, 4, 5, or 6, as valency permits;
each instance of R9 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2;
each instance of RN9 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

### Claim 153 (depends on 152)

The compound of claim 152, wherein RAN is of one of the following formulae:

### Claim 154 (depends on 52, 153)

The compound of any one of claims 52-153, wherein RN9 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.

### Claim 155 (depends on 154)

The compound of claim 154, wherein RN9 is hydrogen.

### Claim 156 (depends on 154)

The compound of claim 154, wherein RN9 is unsubstituted alkyl.

### Claim 157 (depends on 156)

The compound of claim 156, wherein RN9 is methyl.

### Claim 158 (depends on 154)

The compound of claim 154, wherein RN9 is a nitrogen protecting group.

### Claim 159 (depends on 158)

The compound of claim 158, wherein RN9 is acetyl.

### Claim 160 (depends on 158)

The compound of claim 158, wherein RN9 is —SO2—CH3.

### Claim 161 (depends on 118)

The compound of claim 118, wherein RAN is optionally substituted carbocyclyl.

### Claim 162 (depends on 161)

The compound of claim 161, wherein RAN is cyclopentyl.

### Claim 163 (depends on 118)

The compound of claim 118, wherein RAN is optionally substituted heterocyclyl.

### Claim 164 (depends on 163)

The compound of claim 163, wherein RAN is tetrahydropyranyl or piperidine.

### Claim 165 (depends on 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164)

The compound of any one of claims 112-164, wherein RA1 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

### Claim 166 (depends on 165)

The compound of claim 165, wherein RA2 is hydrogen.

### Claim 167 (depends on 165)

The compound of claim 165, wherein RA2 is substituted C1-6 alkyl.

### Claim 168 (depends on 167)

The compound of claim 167, wherein RA2 is optionally substituted —C1-4alkyl-aryl.

### Claim 169 (depends on 168)

The compound of claim 168, wherein RA2 is optionally substituted —CH2-monosubstituted-phenyl.

### Claim 170 (depends on 169)

The compound of claim 169, wherein RA2 is

### Claim 171 (depends on 165)

The compound of claim 165, wherein RA2 is substituted phenyl.

### Claim 172 (depends on 171)

The compound of claim 171, wherein RA2 is o-methoxy-phenyl.

### Claim 173 (depends on 165)

The compound of claim 165, wherein RA2 is optionally substituted heteroaryl.

### Claim 174 (depends on 173)

The compound of claim 173, wherein RA2 is quinolinyl.

### Claim 175 (depends on 114)

The compound of claim 114, wherein z is 0.

### Claim 176 (depends on 114)

The compound of claim 114, wherein z is 1.

### Claim 177 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein Ring A is one of the following formulae:
wherein:
each instance of R10 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2;
r is 0, 1, 2, 3, or 4, as valency permits; and
each instance of RN10 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

### Claim 178 (depends on 177)

The compound of claim 177, wherein Ring A is of the formula:

### Claim 179 (depends on 178)

The compound of claim 178, wherein each instance of R10 is independently optionally substituted C1-6 alkyl or optionally substituted six-membered heterocyclyl.

### Claim 180 (depends on 179)

The compound of claim 179, wherein each instance of R10 is independently unsubstituted C1-6 alkyl or unsubstituted six-membered heterocyclyl.

### Claim 181 (depends on 180)

The compound of claim 180, wherein R10 is isopropyl or morpholinyl.

### Claim 182 (depends on 178, 179, 180, 181)

The compound of any one of claims 178-181, wherein R1\110 is hydrogen.

### Claim 183 (depends on 177)

The compound of claim 177, wherein Ring A is of the formula:

### Claim 184 (depends on 183)

The compound of claim 183, wherein RN10 is optionally substituted C1-6 alkyl.

### Claim 185 (depends on 184)

The compound of claim 184, wherein RN10 is substituted C1-6 alkyl.

### Claim 186 (depends on 185)

The compound of claim 185, wherein RN10 is —C1-6alkyl-heterocyclyl.

### Claim 187 (depends on 186)

The compound of claim 186, wherein RN10 is —CH2-tetrahydropyranyl.

### Claim 188 (depends on 183, 184, 185, 186, 187)

The compound of any one of claims 183-187, wherein R10 is halogen or optionally substituted carbocyclyl.

### Claim 189 (depends on 183, 184, 185, 186, 187)

The compound of any one of claims 183-187, wherein R10 is halogen or optionally substituted C3-6 carbocyclyl.

### Claim 190 (depends on 189)

The compound of claim 189, wherein R10 is cyclopropyl.

### Claim 191 (depends on 189)

The compound of claim 189, wherein R10 is Br.

### Claim 192 (depends on 177)

The compound of claim 177, wherein Ring A is of one of the following formulae:
wherein:
each of R10a and R10b is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2; and
each instance of RN10 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

### Claim 193 (depends on 192)

The compound of claim 192, wherein each instance of RN10 is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl.

### Claim 194 (depends on 192, 193)

The compound of any one of claims 192-193, wherein RN10 is hydrogen.

### Claim 195 (depends on 192, 193)

The compound of any one of claims 192-193, wherein RN10 is optionally substituted C1-6 alkyl.

### Claim 196 (depends on 195)

The compound of claim 195, wherein RN10 is unsubstituted C1-6 alkyl.

### Claim 197 (depends on 196)

The compound of claim 196, wherein RN10 is methyl, ethyl, isopropyl, or tert-butyl.

### Claim 198 (depends on 195)

The compound of claim 195, wherein RN10 is substituted C1-6 alkyl.

### Claim 199 (depends on 198)

The compound of claim 198, wherein RN10 is C1-6 haloalkyl, —C1-4alkyl-cyano, —C1-4 alkyl-alkenyl, —C1-4alkyl-aryl, —C1-4alkyl-carbocyclyl, or —C1-4alkyl-heteroaryl.

### Claim 200 (depends on 199)

The compound of claim 199, wherein RN10 is —CH2—CF3, —CH2—CN, —CH2—CH═CH2, —CH2-pyridinyl, —CH2-cyclopropyl, —CH2-phenyl, or —CH2-o-F-phenyl.

### Claim 201 (depends on 192, 193)

The compound of claims 192-193, wherein RN10 is optionally substituted carbocyclyl.

### Claim 202 (depends on 201)

The compound of claim 201, wherein RN10 is cyclobutyl or cyclopropyl.

### Claim 203 (depends on 192, 193)

The compound of claims 192-193, wherein RN10 is optionally substituted heterocyclyl.

### Claim 204 (depends on 203)

The compound of claim 203, wherein RN10 is tetrahydropyranyl.

### Claim 205 (depends on 192, 193)

The compound of claims 192-193, wherein RN10 is optionally substituted heteroaryl.

### Claim 206 (depends on 205)

The compound of claim 205, wherein RN10 is pyridinyl.

### Claim 207 (depends on 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206)

The compound of any one of claims 192-206, wherein R10a is hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, or —NRBC(═O)N(RB)2.

### Claim 208 (depends on 207)

The compound of claim 207, wherein R10a is hydrogen.

### Claim 209 (depends on 207)

The compound of claim 207, wherein R10a is halogen.

### Claim 210 (depends on 209)

The compound of claim 209, wherein R10a is Cl.

### Claim 211 (depends on 207)

The compound of claim 207, wherein R10a is CN.

### Claim 212 (depends on 207)

The compound of claim 207, wherein R10a is optionally substituted C1-6 alkyl.

### Claim 213 (depends on 212)

The compound of claim 212, wherein R10a is unsubstituted C1-6 alkyl.

### Claim 214 (depends on 213)

The compound of claim 213, wherein R10a is methyl, ethyl, n-propyl, or isopropyl.

### Claim 215 (depends on 212)

The compound of claim 212, wherein R10a is substituted C1-6 alkyl.

### Claim 216 (depends on 215)

The compound of claim 215, wherein R10a is C1-6 haloalkyl.

### Claim 217 (depends on 216)

The compound of claim 216, wherein R10a is CF3.

### Claim 218 (depends on 215)

The compound of claim 215, wherein R10a is —C1-6alkyl-OH.

### Claim 219 (depends on 218)

The compound of claim 218, wherein R10a is —CH2OH.

### Claim 220 (depends on 215)

The compound of claim 215, wherein R10a is of the formula:
wherein X10a is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

### Claim 221 (depends on 220)

The compound of claim 220, wherein X10a is unsubstituted C1-6 alkyl.

### Claim 222 (depends on 221)

The compound of claim 221, wherein X10a is ethyl.

### Claim 223 (depends on 222)

The compound of claim 222, wherein X10a is unsubstituted six-membered heteroaryl.

### Claim 224 (depends on 223)

The compound of claim 223, wherein X10a is pyridinyl.

### Claim 225 (depends on 220)

The compound of claim 220, wherein X10a is unsubstituted heterocyclyl.

### Claim 226 (depends on 225)

The compound of claim 225, wherein X10a is tetrahydropyranyl.

### Claim 227 (depends on 220)

The compound of claim 220, wherein R10a is optionally substituted alkenyl.

### Claim 228 (depends on 227)

The compound of claim 227, wherein R10a is of the formula

### Claim 229 (depends on 220)

The compound of claim 220, wherein R10a is optionally substituted aryl.

### Claim 230 (depends on 229)

The compound of claim 229, wherein R10a is optionally substituted phenyl.

### Claim 231 (depends on 230)

The compound of claim 230, wherein R10a is p-OH-phenyl or p-F-phenyl.

### Claim 232 (depends on 220)

The compound of claim 220, wherein R10a is optionally substituted heterocyclyl.

### Claim 233 (depends on 232)

The compound of claim 232, wherein R10a is optionally substituted four-membered, five-membered, or six-membered heterocyclyl.

### Claim 234 (depends on 233)

The compound of claim 233, wherein R10a is of one of the following formulae:
wherein:
e is 0, 1, 2, 3, or 4, as valency permits; and
each instance of RE is independently hydrogen, halogen, —CN, —NO2, —N3, —OH, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, or optionally substituted amino.

### Claim 235 (depends on 234)

The compound of claim 234, wherein e is 0.

### Claim 236 (depends on 234)

The compound of claim 234, wherein e is 1.

### Claim 237 (depends on 234, 235, 236)

The compound of any one of claims 234-236, wherein RE is CN or optionally substituted alkyl.

### Claim 238 (depends on 237)

The compound of claim 237, wherein RE is CN.

### Claim 239 (depends on 237)

The compound of claim 237, wherein RE is substituted alkyl.

### Claim 240 (depends on 239)

The compound of claim 239, wherein RE is CF3 or methoxy.

### Claim 241 (depends on 234, 235, 236, 237, 238, 239, 240)

The compound of any one of claims 234-240, wherein R10a is one of the following formulae:

### Claim 242 (depends on 207)

The compound of claim 207, wherein R10a is optionally substituted heteroaryl.

### Claim 243 (depends on 242)

The compound of claim 242, wherein R10a is optionally substituted five-membered heteroaryl.

### Claim 244 (depends on 243)

The compound of claim 243, wherein R10a is thiophenyl, furanyl, thiazolyl, or pyrazolyl.

### Claim 245 (depends on 244)

The compound of claim 244, wherein R10a is one of the following formulae:

### Claim 246 (depends on 242)

The compound of claim 242, wherein R10a is optionally substituted six-membered heteroaryl.

### Claim 247 (depends on 246)

The compound of claim 246, wherein R10a is pyridinyl.

### Claim 248 (depends on 207)

The compound of claim 207, wherein R10a is —ORA; and RA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or an oxygen protecting group.

### Claim 249 (depends on 248)

The compound of claim 248, wherein RA is unsubstituted C1-6 alkyl.

### Claim 250 (depends on 249)

The compound of claim 249, wherein RA is methyl or ethyl.

### Claim 251 (depends on 248)

The compound of claim 248, wherein RA is substituted C1-6 alkyl.

### Claim 252 (depends on 251)

The compound of claim 251, wherein RA is C1-6 haloalkyl or —C1-6 alkyl-carbocyclyl.

### Claim 253 (depends on 252)

The compound of claim 252, wherein RA is —CH2—CF3 or —CH2-cyclopropyl.

### Claim 254 (depends on 248)

The compound of claim 248, wherein RA is optionally substituted phenyl.

### Claim 255 (depends on 254)

The compound of claim 254, wherein RA is unsubstituted phenyl.

### Claim 256 (depends on 248)

The compound of claim 248, wherein RA is optionally substituted heterocyclyl.

### Claim 257 (depends on 248)

The compound of claim 248, wherein RA is unsubstituted five-membered heterocyclyl or unsubstituted six-membered heterocyclyl.

### Claim 258 (depends on 257)

The compound of claim 257, wherein RA is tetrahydrofuranyl or tetrahydropyranyl.

### Claim 259 (depends on 207)

The compound of claim 207, wherein R10a is —N(RB)2; and each instance of RB is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

### Claim 260 (depends on 259)

The compound of claim 259, wherein R10a is —NHRB.

### Claim 261 (depends on 259)

The compound of claim 259, wherein R10a is —N(CH3)RB.

### Claim 262 (depends on 259, 260, 261)

The compound of any one of claims 259-261, wherein RB is hydrogen.

### Claim 263 (depends on 259, 260, 261)

The compound of any one of claims 259-261, wherein RB is unsubstituted C1-6 alkyl.

### Claim 264 (depends on 263)

The compound of claim 263, wherein RB is methyl or ethyl.

### Claim 265 (depends on 259, 260, 261)

The compound of any one of claims 259-261, wherein RB is substituted C1-6 alkyl.

### Claim 266 (depends on 265)

The compound of claim 265, wherein RB is optionally substituted —C1-4alkyl-carbocyclyl, optionally substituted —C1-4alkyl-heteroaryl, optionally substituted —C1-4alkyl-heterocyclyl, or optionally substituted —C1-4alkyl-CO2X10B; and X10B is hydrogen or optionally substituted alkyl.

### Claim 267 (depends on 266)

The compound of claim 266, wherein RB is one of the following formulae:

### Claim 268 (depends on 259, 260, 261)

The compound of any one of claims 259-261, wherein RB is optionally substituted C3-6 carbocyclyl.

### Claim 269 (depends on 268)

The compound of claim 268, wherein RB is cyclopropyl.

### Claim 270 (depends on 259, 260, 261)

The compound of any one of claims 259-261, wherein RB is optionally substituted heterocyclyl.

### Claim 271 (depends on 270)

The compound of claim 270, wherein RB is tetrahydropyranyl or oxetanyl.

### Claim 272 (depends on 259, 260, 261)

The compound of any one of claims 259-261, wherein RB is optionally substituted heteroaryl.

### Claim 273 (depends on 272)

The compound of claim 272, wherein RB is optionally substituted thiazolyl.

### Claim 274 (depends on 273)

The compound of claim 273, wherein RB is of the formula

### Claim 275 (depends on 259, 260, 261)

The compound of any one of claims 259-261, wherein RB is a nitrogen protecting group.

### Claim 276 (depends on 275)

The compound of claim 275, wherein:
RB is —SO2—X10S;
X10S is optionally substituted alkyl or —N(RSB)2; and
each instance of RSB is hydrogen or optionally substituted alkyl.

### Claim 277 (depends on 276)

The compound of claim 276, wherein RB is —SO2—N(CH3)2, —SO2—CH3, —SO2—C2H5, or —SO2—CF3.

### Claim 278 (depends on 207)

The compound of claim 207, wherein R10a is —C(═O)N(RB)2; and each instance of RB is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or two RB taken together with the intervening nitrogen form optionally substituted heterocyclyl.

### Claim 279 (depends on 278)

The compound of claim 278, wherein R10a is —C(═O)NHRB.

### Claim 280 (depends on 78)

The compound of claim 78, wherein R10a is —C(═O)N(CH3)RB.

### Claim 281 (depends on 278, 279, 280)

The compound of any one of claims 278-280, wherein RB is hydrogen.

### Claim 282 (depends on 278, 279, 280)

The compound of any one of claims 278-280, wherein RB is optionally substituted C1-6 alkyl.

### Claim 283 (depends on 282)

The compound of claim 282, wherein RB is unsubstituted C1-6 alkyl.

### Claim 284 (depends on 283)

The compound of claim 283, wherein RB is methyl or ethyl.

### Claim 285 (depends on 282)

The compound of claim 282, wherein RB is substituted C1-6 alkyl.

### Claim 286 (depends on 285)

The compound of claim 285, wherein RB is C1-6 haloalkyl.

### Claim 287 (depends on 286)

The compound of claim 286, wherein RB is —CH2—CF3.

### Claim 288 (depends on 285)

The compound of claim 285, wherein RB is optionally substituted —C1-4alkyl-carbocyclyl.

### Claim 289 (depends on 288)

The compound of claim 288, wherein RB is —CH2-cyclopropyl.

### Claim 290 (depends on 285)

The compound of claim 285, wherein RB is optionally substituted —C1-4alkyl-heteroaryl.

### Claim 291 (depends on 290)

The compound of claim 290, wherein RB is one of the following formulae:

### Claim 292 (depends on 285)

The compound of claim 285, wherein RB is optionally substituted —C1-4alkyl-heterocyclyl.

### Claim 293 (depends on 92)

The compound of claim 92, wherein RB is one of the following formulae:

### Claim 294 (depends on 285)

The compound of claim 285, wherein RB is optionally substituted —C1-4alkyl-phenyl.

### Claim 295 (depends on 294)

The compound of claim 294, wherein RB is one of the following formulae:

### Claim 296 (depends on 278, 279, 280)

The compound of claims 278-280, wherein RB is optionally substituted carbocyclyl.

### Claim 297 (depends on 297)

The compound of claim 297, wherein RB is cyclopropyl.

### Claim 298 (depends on 278, 279, 280)

The compound of claims 278-280, wherein RB is optionally substituted heterocyclyl.

### Claim 299 (depends on 298)

The compound of claim 298, wherein RB is tetrahydrofuranyl or tetrahydropyranyl.

### Claim 300 (depends on 299)

The compound of claim 299, wherein two RB taken together with the intervening nitrogen form an optionally substituted heterocyclyl.

### Claim 301 (depends on 300)

The compound of claim 300, wherein R10a is one of the following formulae:

### Claim 302 (depends on 207)

The compound of claim 207, wherein R10a is —C(═O)ORA; and RA is optionally substituted alkyl.

### Claim 303 (depends on 302)

The compound of claim 302, wherein lea is —C(═O)OC2H5.

### Claim 304 (depends on 207)

The compound of claim 207, wherein R10a is —C(═O)RA; and RA is optionally substituted alkyl.

### Claim 305 (depends on 304)

The compound of claim 304, wherein R10a is —C(═O)C2H5.

### Claim 306 (depends on 207)

The compound of claim 207, wherein R10a is —NRBC(═O)ORA; RA is optionally substituted alkyl; and RB is hydrogen or optionally substituted alkyl.

### Claim 307 (depends on 306)

The compound of claim 306, wherein RB is hydrogen.

### Claim 308 (depends on 306)

The compound of claim 306, wherein RA is unsubstituted C1-6 alkyl.

### Claim 309 (depends on 308)

The compound of claim 308, wherein RA is methyl or ethyl.

### Claim 310 (depends on 306)

The compound of claim 306, wherein RA is substituted C1-6 alkyl.

### Claim 311 (depends on 310)

The compound of claim 310, wherein RA is C1-6 alkyl-aryl.

### Claim 312 (depends on 311)

The compound of claim 311, wherein RA is —CH2-Ph.

### Claim 313 (depends on 207)

The compound of claim 207, wherein R10a is —NRBC(═O)N(RB)2; and each instance of RB is hydrogen; optionally substituted alkyl; or optionally substituted heterocyclyl.

### Claim 314 (depends on 313)

The compound of claim 313, wherein R10a is —NHC(═O)N(RB)2.

### Claim 315 (depends on 314)

The compound of claim 314, wherein R10a is —NHC(═O)NHRB or —NHC(═O)N(CH3)RB.

### Claim 316 (depends on 313, 314, 315)

The compound of any one of claims 313-315, wherein RB is unsubstituted C1-6 alkyl.

### Claim 317 (depends on 316)

The compound of claim 316, wherein RB is methyl, ethyl, or isopropyl.

### Claim 318 (depends on 313, 314, 315)

The compound of any one of claims 313-315, wherein RB is optionally substituted heterocyclyl.

### Claim 319 (depends on 318)

The compound of claim 318, wherein RB is tetrahydropyranyl.

### Claim 320 (depends on 207)

The compound of claim 207, wherein R10a is —C(═O)N(RB)2; and each instance of RB is hydrogen or optionally substituted alkyl.

### Claim 321 (depends on 320)

The compound of claim 320, wherein R10a is —C(═O)NHRB.

### Claim 322 (depends on 321)

The compound of claim 321, wherein RB is optionally substituted C1-6alkyl-heteroaryl or optionally substituted C1-6alkyl-heterocyclyl.

### Claim 323 (depends on 320, 321, 322)

The compound of any one of claims 320-322, wherein RB is of the formula:
wherein:
v is 1, 2, 3, 4, 5, 6, or 7; and
X11 is optionally substituted heterocyclyl or optionally substituted five-membered heteroaryl.

### Claim 324 (depends on 323)

The compound of claim 323, wherein RB is of one of the following formulae:

### Claim 325 (depends on 323, 324)

The compound of any one of claims 323-324, wherein v is 2.

### Claim 326 (depends on 323, 324)

The compound of claims 323-324, wherein v is 3.

### Claim 327 (depends on 323, 324)

The compound of claims 323-324, wherein v is 4.

### Claim 328 (depends on 323, 324)

The compound of claims 323-324, wherein v is 5.

### Claim 329 (depends on 207, 328)

The compound of any one of claims 207-328, wherein R10b is hydrogen or optionally substituted C1-6 alkyl.

### Claim 330 (depends on 329)

The compound of claim 329, wherein R10b is hydrogen.

### Claim 331 (depends on 329)

The compound of claim 329, wherein R10b is unsubstituted C1-6 alkyl.

### Claim 332 (depends on 331)

The compound of claim 331, wherein R10b is methyl.

### Claim 333 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein Ring A is one of the following formulae:
wherein:
each instance of R12 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2;
w is 0, 1, or 2; and
each instance of RN12 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

### Claim 334 (depends on 333)

The compound of claim 333, wherein Ring A is one of the following formulae

### Claim 335 (depends on 333, 334)

The compound of any one of claims 333-334, wherein RN12 is hydrogen or optionally substituted alkyl.

### Claim 336 (depends on 335)

The compound of claim 335, wherein RN12 is hydrogen.

### Claim 337 (depends on 336)

The compound of claim 336, wherein RN12 is optionally substituted C1-6 alkyl.

### Claim 338 (depends on 337)

The compound of claim 337, wherein RN12 is unsubstituted C1-6 alkyl.

### Claim 339 (depends on 338)

The compound of claim 338, wherein RN12 is isopropyl or tert-butyl.

### Claim 340 (depends on 333, 334, 335, 336, 337, 338, 339)

The compound of any one of claims 333-339, wherein R′2 is —N(RB)2 or —C(═O)N(RB)2, wherein each instance of RB is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

### Claim 341 (depends on 333, 334, 335, 336, 337, 338, 339, 340)

The compound of any one of claims 333-340, wherein R′2 is —NHRB, —N(CH3)RB, —C(═O)NHRB, or, —C(═O)N(CH3)RB.

### Claim 342 (depends on 333, 334, 335, 336, 337, 338, 339, 340, 341)

The compound of any one of claims 333-341, wherein RB is hydrogen.

### Claim 343 (depends on 333, 334, 335, 336, 337, 338, 339, 340, 341)

The compound of any one of claims 333-341, wherein RB is optionally substituted C1-6 alkyl.

### Claim 344 (depends on 343)

The compound of claim 343, wherein RB is unsubstituted C1-6 alkyl.

### Claim 345 (depends on 344)

The compound of claim 344, wherein RB is methyl.

### Claim 346 (depends on 343)

The compound of claim 343, wherein RB is substituted C1-6 alkyl.

### Claim 347 (depends on 346)

The compound of claim 346, wherein RB is optionally substituted —C1-6 alkyl-heterocyclyl or optionally substituted —C1-6 alkyl-heteroaryl.

### Claim 348 (depends on 347)

The compound of any one of claim 347, wherein RB is one of the following formulae:

### Claim 349 (depends on 334, 335, 336, 337, 338, 339, 340, 341)

The compound of any one of claims 334-341, wherein RB is optionally substituted carbocyclyl.

### Claim 350 (depends on 349)

The compound of claim 349, wherein RB is cyclopropyl.

### Claim 351 (depends on 334, 335, 336, 337, 338, 339, 340, 341)

The compound of any one of claims 334-341, wherein RB is optionally substituted heterocyclyl.

### Claim 352 (depends on 351)

The compound of claim 351, wherein RB is unsubstituted heterocyclyl.

### Claim 353 (depends on 352)

The compound of claim 352, wherein RB is tetrahydropyranyl.

### Claim 354 (depends on 1, 353)

The compound of any one of claims 1-353, wherein IV is optionally substituted C1-4 alkyl.

### Claim 355 (depends on 354)

The compound of claim 354, wherein IV is unsubstituted C1-4 alkyl.

### Claim 356 (depends on 355)

The compound of claim 355, wherein IV is methyl.

### Claim 357 (depends on 1, 356)

The compound of any one of claims 1-356, wherein R3a is hydrogen.

### Claim 358 (depends on 1, 357)

The compound of any one of claims 1-357, wherein R3a is optionally substituted C1-4 alkyl.

### Claim 359 (depends on 358)

The compound of claim 358, wherein R3a is unsubstituted C1-4 alkyl.

### Claim 360 (depends on 359)

The compound of claim 359, wherein R3a is methyl.

### Claim 361 (depends on 1, 360)

The compound of any one of claims 1-360, wherein R3b is hydrogen.

### Claim 362 (depends on 1, 361)

The compound of any one of claims 1-361, wherein R3b is optionally substituted C1-4 alkyl.

### Claim 363 (depends on 362)

The compound of claim 362, wherein R3b is methyl.

### Claim 364 (depends on 1, 363)

The compound of any one of claims 1-363, wherein R3b is optionally substituted C3-4 cyclcoalkyl.

### Claim 365 (depends on 364)

The compound of claim 364, wherein R3b is cyclopropyl.

### Claim 366 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of the compounds depicted in Table 1, and pharmaceutically acceptable salts thereof.

### Claim 367 (depends on 1)

The compound of claim 1, wherein the compound is not one of the compounds depicted in Table 2.

### Claim 368 (depends on 1, 367)

A pharmaceutical composition comprising a compound of any one of claims 1-367 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 369 (depends on 1, 367)

A kit or packaged pharmaceutical comprising a compound of any one of claims 1-367 or a pharmaceutically acceptable salt thereof, and instructions for use thereof.

### Claim 370 (depends on 1, 367)

A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of any one of claims 1-367 or a pharmaceutically acceptable salt thereof.

### Claim 371 (depends on 370)

The method of claim 370, wherein the arginine methyl transferase is PRMT1.

### Claim 372 (depends on 370)

The method of claim 370, wherein the arginine methyl transferase is PRMT6.

### Claim 373 (depends on 370)

The method of claim 370, wherein the arginine methyl transferase is PRMT3.

### Claim 374 (depends on 370)

The method of claim 370, wherein the arginine methyl transferase is PRMT8.

### Claim 375 (depends on 70)

The method of claim 70, wherein the arginine methyl transferase is CARM1.

### Claim 376 (depends on 1, 367)

A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of any one of claims 1-367 or a pharmaceutically acceptable salt thereof.

### Claim 377 (depends on 1, 367)

A method of modulating transcription comprising contacting a cell with an effective amount of a compound of any one of claims 1-367 or a pharmaceutically acceptable salt thereof.

### Claim 378 (depends on 370, 371, 372, 373, 374, 375, 376, 377)

The method of any one of claims 370-377, wherein the cell is in vitro.

### Claim 379 (depends on 370, 371, 372, 373, 374, 375, 376, 377)

The method of any one of claims 370-377, wherein the cell is in a subject.

### Claim 380 (depends on 1, 367, 368)

A method of treating a RMT-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-367, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 368.

### Claim 381 (depends on 380)

The method of claim 380, wherein the RMT-mediated disorder is a PRMT1-mediated disorder.

### Claim 382 (depends on 380)

The method of claim 380, wherein the RMT-mediated disorder is a PRMT6-mediated disorder.

### Claim 383 (depends on 380)

The method of claim 380, wherein the RMT-mediated disorder is a PRMT3-mediated disorder.

### Claim 384 (depends on 380)

The method of claim 380, wherein the RMT-mediated disorder is a PRMT8-mediated disorder.

### Claim 385 (depends on 380)

The method of claim 380, wherein the RMT-mediated disorder is a CARM1-mediated disorder.

### Claim 386 (depends on 380)

The method of claim 380, wherein the disorder is a proliferative disorder.

### Claim 387 (depends on 386)

The method of claim 386, wherein the disorder is cancer.

### Claim 388 (depends on 380)

The method of claim 380, wherein the disorder is a neurological disorder.

### Claim 389 (depends on 388)

The method of claim 388, wherein the disorder is amyotrophic lateral sclerosis.

### Claim 390 (depends on 380)

The method of claim 380, wherein the disorder is a muscular dystrophy.

### Claim 391 (depends on 380)

The method of claim 380, wherein the disorder is an autoimmune disorder.

### Claim 392 (depends on 380)

The method of claim 380, wherein the disorder is a vascular disorder.

### Claim 393 (depends on 380)

The method of claim 380, wherein the disorder is a metabolic disorder.